Ketamine, an N-methyl-D-aspartate receptor antagonist, is widely known as a dissociative anesthetic and phencyclidine derivative. Due to an undesirable adverse event profile when used as an anesthetic it had widely fallen out of human use in favor of more modern agents. However, it has recently been explored for several other indications such as treatment resistant depression and chronic pain. Several recent studies and case reports compiled here show that ketamine is an effective analgesic in chronic pain conditions including cancer-related neuropathic pain. Of special interest is ketamine’s opioid sparing ability by counteracting the central nervous system sensitization seen in opioid induced hyperalgesia. Furthermore, at the sub-anesthetic concentrations used for analgesia ketamine’s safety and adverse event profiles are much improved. In this article, we review both the basic science and clinical evidence regarding ketamine’s utility in chronic pain conditions as well as potential adverse events. Ketamine, a phencyclidine derivative, was first synthesized in the 1960s as a short-acting alternative to phencyclidine which also demonstrated lower occurrence rates of emergence delirium . The dru, due to an asymmetric C2 carbon atom. It exhibits non-polarity and is therefore highly lipid soluble. While both the racemate mixture and (S)-Ketamine are clinically available as water soluble powders, there are currently no commercial (R)-Ketamine solutions. This is likely due to the observation that (S)-Ketamine is several times more potent at producing anesthetic and analgesic effects -2-(methylamino)-cyclohexanone ketamine. It consists of two optical enantiomers, both of which can be seen in  effects .In a study of healthy patients, the volume of distribution is estimated as 380–650 L/70 kg while the oral bioavailability was found to be in the range of 7–20%. The low bioavailability is due to a high first pass metabolism evidenced by the fact that clearance of ketamine was 83–121 L/h/70 kg which is in the range of liver blood flow. It can therefore be deduced that conditions such as cirrhosis which reduce hepatic blood flow will lower ketamine clearance .Initial metabolism of ketamine occurs via oxidation by the cytochrome P450 family of enzymes, most notably CYP3A4 and CYP2B6, which produces norketamine, 6-hydroxyketamine, and 4-hydroxyketamine. Norketamine retains pharmacologic activity and is considered the major metabolite as approximately 80% of ketamine is metabolized to this form. The remaining 20% is metabolized by one of two pathways to 4- or 6-hydroxyketamine before subsequently metabolized to hydroxy-norketamine .Ketamine has been shown to have interactions on the metabolism and activity of many other drugs that must be considered when used clinically. Of special note is ketamine’s reliance on the cytochrome P450 family of enzymes for its metabolism and degradation.Rifampin, a well-known inducer of the CYP3A subfamily of enzymes, greatly reduces the area under the curve (AUC) for ketamine plasma concentration  and reduced the maximum plasma concentration after oral ketamine by 81% while not significantly shortening half-life of the drug .In contrast, patients given Clarithromycin demonstrated a 2.6-fold increase in maximum Ketamine plasma concentration due to inhibition of the enzyme CYP3A resulting in a self-reported increase in drug efficacy . GrapefrIn addition to effects on the P450 family of enzymes, ketamine also inhibits many human UDP-glucuronosyltransferase (UGT) enzymes with the exception of UGT1A4. UGT2B4, UGT2B7, and UGT2B15 were inhibited with IC50’s less than <100 μM ketamine. Of specific interests, inhibition of UGT2B7 is responsible for metabolism of Morphine and Codeine. At anesthetic doses, inhibition of this enzyme was clinically significant for metabolism for Morphine and Codeine while at analgesic doses the inhibition was only clinically significant for Codeine metabolism .Another important drug interaction occurs with benzodiazepines which are frequently used to reduce dissociative symptoms of ketamine. Pre-treatment of surgical patients with diazepam results in higher plasma concentrations of ketamine and decreased ketamine clearance . Pre-treWith the increasing field-wide focus on personalized medicine, much work has also been done to understand how genetics can impact the metabolism and clearance of ketamine. Due to the wealth of information and availability of genetic information the cytochrome P450 family, especially CYP3A4 and CYP2B6 enzymes, have been the focus of much research.One study surveyed the catalytic activity of thirty-eight CYP2C9 alleles on ketamine metabolism to norketamine. Compared with 2C9*1, three alleles  demonstrated dramatically increased intrinsic clearance (1.2-fold–3.75-fold); four subtypes  exhibited no significant change on enzyme activity. The remaining 31 alleles expressed different degrees of reduction compared with wild type .in vitro study demonstrated that genetic variations in the CYP2B6 gene caused significant differences in plasma clearance of ketamine as well as in the ratio of norketamine: ketamine metabolic ratios. Specifically, those with the CYP2B6*6/*6 genotype exhibited a significantly lower plasma clearance of ketamine and norketamine: ketamine ratio when compared with both the CYP2B6*6/*1 and CYP2B*1/*1 genotypes (p < 0.05) (Another  < 0.05) .With this information, CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine and norketamine were determined using High Performance Liquid Chromatography (HPLC). Patients with the CYP2B6*6 allele demonstrated a substantial decrease in steady-state ketamine plasma clearance . This deThe importance of the CYP2B6 gene was confirmed by another study which demonstrated that per molecule the enzymatic activity of the CYP2B6 gene product was higher than that of CYP3A4 or CYP2C9 when comparing N-demethylation of ketamine to norketamine. However, the same study demonstrated that when adjusted for the average relative content of these three enzymes in human hepatocytes CYP3A4 is the principle enzyme of ketamine metabolism at therapeutic concentrations due to is ∼30-fold higher abundance . UnfortuKetamine’s mechanism of action is widely regarded as one of pharmacology’s most complex due to its interaction with multiple binding sites including NMDA receptors, opioid receptors, Na channels, and L-type calcium channels ..The primary anesthetic effect of ketamine is associated with NMDA receptor blockade which utilizes an uncompetitive mechanism with a relatively long knock-off time. Blockade of NMDA receptors disrupts normal excitatory glutamate signaling in the CNS and is associated with many anesthetic agents. A depiction of ketamine’s action on the NMDA receptor can be seen in 2 binding sites and significantly inhibits their uptake. Affinity of ketamine for the 5-HT site is equal to that of ketamine for NMDA receptors. Affinity for the D2 site is 1/3rd of that  corresponded to development of neuropathic pain behavior. Meanwhile, administration of minocycline  and pentoxifylline (cytokine release inhibitor) reduced CCI-related hypersensitivity . LikewisThe increased use ketamine in neuropathic has been fueled by research indicating that ketamine may not only provide analgesia for these conditions but also stop the development and advancement of neuropathic pain at its source. For example, a mouse spinal nerve ligation (SNL) model demonstrated that ketamine administration inhibits astrocyte activation and down-regulates expression of GFAP protein X. .Ketamine may also play a role in decreasing neuronal inflammation by inhibiting cytokine release as ketamine reduces LPS-induced TNF-a production in mixed glial cell cultures .Other models have shown that administration of S-ketamine entirely inhibited pharmacologically induced tactile allodynia via inhibition of Voltage-Gated Calcium Dependent (BK) Potassium Channels leading to decreased mIL-1B and BDNF secretion and reduced glial activation. Another known inhibitor of this channel, charybdotoxin, was shown to significantly reduce nerve injury induced tactile allodynia in mice .While the exact mechanism of Opioid Induced Hyperalgesia (OIH) is unknown, one of the leading theories is overactivation and stimulation of the NMDA-receptor. OIH is more commonly observed following high-dose opioid administration such as that used for refractory cancer pain. This proposed mechanism would explain why NMDA Receptor modulators such as ketamine are effective in treating the condition .One study proving this efficacy demonstrated that compared to those who underwent anesthesia with high-dose remifentanil only, patients receiving high-dose remifentanil and intra-operative ketamine infusion experienced less post-operative hyperalgesia as measured by pain rating at 6 and 24 h and cumulative fentanyl dose before release . In anotTogether, these studies indicate that ketamine may counteract OIH and thereby decreased total daily oral morphine equivalent required for pain management. Clinically, this information has been applied by using ketamine as an agent to reduce total opioid usage perioperatively, treat opioid induce neurotoxicity, and to control pain that has stopped responding to opioid escalation . Given tDue to the frequency of chemotherapy-induced neuropathic pain in cancer patients, an established animal model for this pain condition (paclitaxel-induced neuropathy) was used to determine the potential efficacy of ketamine. In two separate studies systemic ketamine injection ameliorated pain behaviors including mechanical allodynia and thermal hyperalgesia rats . InteresNerve injury-induced neuropathic pain animal models include spinal nerve ligation (SNL), chronic constriction injury (CCI), spared nerve injury (SNI), constriction of the infraorbital nerve, and complete spinal cord transection in animals including rat and mouse.The single systemic injection of ketamine reduced several nociceptive pain behaviors including mechanical allodynia and hyperalgesia, cold allodynia, spontaneous pain in SNL model in rat at dose of 0.01, 1, 5, 10 mg/kg. However, high doses  produced adverse effects including motor impairment . In addiIn the SNI model, repeated injection or systemic infusion of ketamine reduced mechanical and cold allodynia for several weeks at dose of 9 mg/kg/day for 5 days or 3 mg/kg/h for 3 h daily, total for 5 days . HoweverIn the CCI model, systemic injection of ketamine reduced heat hyperalgesia and mechanical allodynia for several hours at a dose of 30, 40, and 50 mg/kg . Its ED2Another condition which frequently manifests with neuropathic pain is chronic diabetes. In mice, this can be modeled with high-dose injection of streptozotocin which selectively kills pancreatic beta cells through DNA alkalization.In two studies of streptozotocin-induced diabetic neuropathy, systemic infusion of ketamine at 20 mg/kg/day for 5 days reduced heat and mechanical hyperalgesia for several weeks following treatment . In one While three of the most common neuropathic pain conditions have been discussed above, there are a multitude more neuropathic pain models available in animals to test the efficacy of ketamine. In various models including arthritic pain, distal tibia fracture and casting, ischemia and reperfusion, and herpetic pain, the systemic injection of ketamine reduced pain behaviors .In the distal tibia fracture and casting in mouse, subcutaneous injections of ketamine (2 mg/kg/day for 7 days starting week 7 after fracture) reduced allodynia for 4 weeks after its termination .In the ischemia and reperfusion models in rat, intraperitoneal injection of ketamine (100 mg/kg) reduced mechanical and cold allodynia .In herpetic pain model using inoculation of Herpes simplex virus type 1 on skin of the femur in female C57BL/6 J mice, intraperitoneal injection of ketamine (50 mg/kg) reduced allodynia on day 7 after inoculation .The success of ketamine in treating such a wide array of neuropathic pain models is promising as it suggests that ketamine is acting to reverse/inhibit a process involved in the general development of neuropathic pain rather than a process which may be specific to a single animal model. A summary of all the discussed basic science and animal model evidence of ketamine's efficacy as an analgesic can be found in The use of ketamine have been reported in various acute pain animal models including writhing, hot plate, formalin and tail-flick test in mice and rats. In various models Ketamine was administered by systemic administrations  or local administrations .Takahashi et al. reported that subcutaneous injection of ketamine  promoted dose-related analgesia in both the acetic acid-induced writhing and hot plate tests in mice. Analgesia was not affected by pretreatment with naloxone (10 mg/kg).Hillhouse and Negus reported that intraperitoneal injection of ketamine (1.0–10.0 mg/kg) blocked lactic acid-stimulated stretching in rats but failed to block lactic acid-induced depression in rats. In addition, higher doses of ketamine (10 mg/kg) depressed behaviors including lactic acid-stimulated stretching and lactic acid-induced depression.Finck et al. showed that the subcutaneous injection of ketamine  reduced the number of writhes in the morphine pellet-implanted mice using the abdominal constriction test. On the other hand, ketamine was found to be much less effective as an analgesic agent in the morphine tolerant mice. The data indicated a possible cross-tolerance between morphine and ketamine.Millan and Seguin reported that in the formalin-induced licking behavior by intraplantar injection of formalin in mice and intraperitoneal injection of ketamine blocked both the early and late phases. The doses of ketamine used were 6.0 mg/kg for early phase and 7.7 mg/kg for late phase.Bulutcu et al. reported that intraperitoneal injection  or intrathecal injection  of ketamine produced dose-dependent antinociceptive effects in the acetic acid-induced writhing and formalin tests but not in the tail-flick nor in hot-plate tests in mice.Lastly, Sawynok and Reid reported that local pretreatment with 10–1,000 nmol ketamine via subcutaneous injection into the dorsal surface of the hind paw had no effect on phase 2 flinching behaviors and phase 2 biting/licking behaviors produced by both 1.5% and 5% formalin. In addition, ketamine produced no effect on phase 1 behaviors. In addition, systemic intraperitoneal injection of ketamine  generally had no effect on phase 1 and 2 flinching behaviors.For much of the drug’s lifespan ketamine has been used primarily as a dissociative anesthetic and a pediatric analgesic for acute pain in the emergency department. However, more recently there has been renewed interest in the drug for potential treatment of refractory pain, substance abuse, and treatment resistant depression. Indeed, both intranasal and oral ketamine have recently garnered FDA approval for the treatment of depression .While the latest Cochrane Review from 2017 found insufficient evidence to recommend Ketamine as an adjunctive therapy in cancer pain, significant clinical evidence is building that demonstrates ketamine as a potent analgesic with a limited adverse event profile .One of the first applications of ketamine for analgesia was via intravenous infusion due to the ability to avoid first-pass metabolism and the well-controlled nature of administration. Additionally, these infusions typically occurred in inpatient settings allowing the healthcare team to monitor for adverse conditions and track treatment efficacy.A meta-analysis including a total of 211 patients in seven different studies revealed a significant analgesic effect for intravenous ketamine infusions in both neuropathic and non-neuropathic pain conditions when compared to placebo. The average infusion duration for these patients was 5 h reaching a median ketamine dose of 0.35 mg/kg. In all seven studies, maximum analgesic effect was observed between 48 h and 2 weeks post-infusion. Magnitude of pain reduction remained significant until 4 weeks post-infusion with some effect seen as far as 8 weeks out. Efficacy of ketamine was not significantly different between pain conditions or classifications. The studies also reported no efficacy difference between ketamine as a standalone or adjuvant therapy. In all seven studies, maximum analgesic effect was observed between 48 h and 2 weeks .Taking the above meta-analysis into consideration, ketamine shows significant promise for the treatment of a wide variety of chronic pain conditions, including neuropathic and non-neuropathic. Furthermore, due to the long-acting nature of ketamine’s analgesia this treatment can be offered outpatient with visits to pain management only required as frequently as infusions are needed.Case studies also support the use of ketamine as a third-line agent in intractable cancer pain. In 12 cancer patients with intractable pain, ketamine infusions at a rate of 1.5 mg/kg/day reduced total daily morphine use by 50% after patients were sent home with ketamine/morphine pain pumps. Side effects were minimal and only occurred with the initial testing dose .In contrast to infusions of ketamine, oral and nasal formulations are commonly administered without direct physician supervision and are therefore more desirable for management of long-term pain conditions. While they require significantly higher doses due to extensive metabolism, oral administrations have also proven effective in providing analgesia.Two studies investigating oral ketamine analgesia both showed at least mild pain reduction. One study with a daily dose of 2 mg/kg ketamine reduced or abolished pain in two-thirds of patients while one-half of patients reported some adverse event. Only half of these patients decided to stop the ketamine therapy. Interestingly, the incidence of adverse events was lower in patients concomitantly taking opioids . The secIn addition to reduction of pain, oral ketamine has also shown promise in countering Opioid-induced Hyperalgesia (OIH). Patients administered oral ketamine (0.5 mg/kg every 12 h) had significantly lower oral morphine consumption than those in a control group. Indicating that ketamine has some analgesic and opioid tolerance sparing ability. Additionally, the ketamine patients reported decreased somnolence perhaps due to the decreased opioid dosing .p = 0.007)  score that was at least 40% lower than pre-treatment levels compared to 20% of placebo patients achieving the same metric (= 0.007) . Other sFor patients in whom systemic ketamine administration via oral or IV routes is not desirable administration of the drug as a topical agent may be possible. As with many drugs, this route provides the benefit of keeping plasma concentrations and therefore potential side effects at a minimum.It is important to note that In addition to the central nervous system, NMDA receptors are widely present in the axons of the peripheral nervous system. In neuropathic and inflammatory pain conditions, topical ketamine alleviates pain by down regulating the upregulated NMDA, AMPA and kinate receptors .One of the most frequent disorders that is treated with a ketamine topical is Chronic Regional Pain Syndrome (CRPS), a type of chronic neuropathic pain. Ketamine creams, both a 10% Ketamine only and a combination of ketamine and several other analgesics have been shown effective in reducing pain measures, tactile allodynia and Visual Analog Scale (VAS) pain score, in these patients in as little as 30 min and in a fraction of patients similar to systemic treatment . These sOthers have also demonstrated that topical ketamine and amitriptyline cream is effective in other pain conditions such as postherpetic neuralgia .While these studies are promising, there are also several studies that seem to contradict their results. Many of the same topical applications mentioned above have been tested and shown no effect in other studies . HoweverDocumented use of ketamine for analgesia in the pediatric population is scarcer, the instances which we do have are promising. Ketamine therapy has been shown effective in a variety of pain conditions in the pediatric population and with a minimal adverse event profile similar to its general population use. Initial animal studies raised concern regarding the toxicity of ketamine to developing neuronal cells. However, these worries have been lessened as more recent studies have demonstrated that the developmental stage at which these animal studies took place correlates to a pre-birth period in humans.A case study of 12 children treated 3x daily with oral ketamine demonstrated results similar to those in adults. Five of the 12 patients experienced significant improvement in pain scores that lasted up to four weeks after the ketamine treatment. Two patients eventually treated at the highest dose of 1.5 mg/kg/dose experienced dose-limiting toxicities and ceased treatment .In another case study of 11 children ranging in age from 3–17 years old with inadequate pain control despite opioid escalation 73% of patients reported subjectively improved pain scores and total opioid consumption was decreased by 28%–100%. These patients were receiving lorazepam concurrently to prevent psychiatric side effects .Likewise, a 13 year-old patient with refractory pain following pancreatitis was treated with hydromorphone until reaching a total daily morphine equivalent of 1,375 mg and being admitted to the ICU. Following a sub-anesthetic administration of IV ketamine average 5 days pain score was rapidly reduced from 8.3 to 4.4 while OME requirements were reduced to 375 mg. The patient experienced no adverse effects from the drug .Finally, a single case report detailing a 14 year old patient with pain refractory to other treatments was admitted to the PICU and administered an infusion of ketamine at 7 μg/kg/minute for 24 h a day. Not only did this patient report a 70% decrease in total pain score, but also a decrease in depressive symptoms. Due to the success of this treatment, the patient was retreated in the same manner when presenting again 5-months later . The mitWhile ketamine is regarded as safe for the general population, the drug may be contraindicated or at least require special precautions for some sub-populations. The first of these is in patients who have a history of schizophrenia, psychotic symptoms, or Post-Traumatic Stress Disorder (PTSD). Ketamine has been shown to exacerbate and/or elicit psychotic symptoms in these patients and its use is therefore non-desirable . When usAnother population that may require special caution is patients with cardiovascular or hepatic compromise. Ketamine has been shown to produce increased cardiac stimulation which may be harmful to patients with previous cardiovascular disease . LikewisFinally, ketamine is widely considered as contraindicated in patients less than 3 months of age due to complications in maintaining a patent airway . While sThe above studies provide significant evidence that ketamine can be safely utilized for its analgesic properties in sub-anesthetic doses. Intravenous and oral/intranasal ketamine proved effective in a wide range of pain conditions including neuropathic pain, CRPS, and acute pain exacerbations. While hypothesized that ketamine may provide special benefits in neuropathic pain, the studies which explicitly examined this found no difference in efficacy based on pain condition. The dosages which provided effective analgesia were also consistent across pain conditions with most studies finding an i. v. infusion of 0.35 mg/kg ketamine effective for analgesia for up to two weeks. For oral ketamine, a daily dose around 1–1.5/kg mg seemed to be the standard and produced effects in >50% of patients.Topical ketamine has much less supporting evidence for its use but several reports detail efficacy in CRPS with minimal systemic absorption and adverse events.The average dosage required for anesthesia in patients is 2 mg/kg as a single bolus over 1 min with anesthesia only lasting 5–10 min . Of the This therapeutic window is also confirmed for oral ketamine by plasma studies which demonstrate that analgesia is obtained at ketamine concentrations of 0.04 μg/ml when taken orally while anesthetic effects are not observed till a range of 0.64–1.12 μg/ml .Sub-anesthetic ketamine infusions were associated with adverse drug events  in 29.5% of patients. This occurrence rate was significantly lower (10.3% vs. 37.3%) in patients diagnosed with depression. The researcher’s hypothesis is that increased NMDA-receptor activity seen in depression is protective against psychotic effects of ketamine .Ketamine has long been known to have cognitive side effects that frequently limit its use. In fact, ketamine was known to produce dissociative and psychomimetic effects within years of its discovery . These cOne of the most prominent cognitive side effects is the sense of a general “euphoria” and disconnection from their surroundings. In a study of healthy volunteers, ketamine administration produced a discernible change in subjective experience in patients including prominence of distant sounds, feelings of dreaminess, loss of attentiveness, and illusory perception of movements. With an oral dose of 25 mg of ketamine, all patients were able to distinguish a feeling of dreaminess/less attentiveness compared to a when receiving a placebo .In addition to these euphoric feelings, ketamine has also been shown to produce a formal thought disorder and impairments in both working and semantic memory function in healthy volunteers . In chroLia et al. showed decreased gray and white matter volumes in the pre-frontal cortex and white matter degeneration in the left temporoparietal lobe  of CRPS patients treated with ketamine infusions for refractory pain experienced transient elevations in lever enzyme  levels that decreased back to baseline within 10–14 days following treatment .. In this way, ketamine acts like a sympathomimetic on the cardiovascular system although exceptions are seen with some critically-ill patients.Isolated human-heart studies have indicated that ketamine acts directly on cardiac myocytes as a concentration-dependent negative inotropic agent. However, due to its central inhibition of norepinephrine reuptake in adrenergic nerves it generally produces an increase in cardiac output via elevations in heart rate, systolic blood pressure, and diastolic blood pressure . In thisAs evidence of the potential magnitude of this effect, a study of 20 healthy volunteers documented a 40–50% increase in total cardiac output when given intravenous infusion of ketamine at analgesic concentrations .While most examples of ketamine acting as a sympathomimetic involve intravenous infusions (largely due to the drugs use in inducing anasthesia), it is also important for analgesia purposes that the oral rout of administration does not negate this sympathomimetic effect.A 67-year-old woman introduced to oral ketamine in the hospital for refractory chronic pain developed uncontrolled hypertension (222/124 mmHg). After release, the patient was not immediately followed up with but the hypertension was found to be persistent by her GP until cessation of the oral ketamine . These fConcern of ketamine’s potential neurotoxicity arise from animal studies demonstrating that ketamine administration in rats results in dose-related and time-related increases in neuronal apoptotic cell death in the frontal cortex and other areas of the brain during development .However, the validity of these studies to humans is frequently challenged. Criticism of the above (and many other ketamine neurotoxicity studies) argues the ketamine neurotoxicity observed in rat studies is not clinically relevant as the stage at which the rat studies take place is during the CNS growth spurt corresponding to 22–26 weeks gestation in humans, therefore humans would never be exposed to ketamine as ketamine is widely regarded as contraindicated <3 years of age .Even so, long-term treatment with ketamine does come with some documented potential for neurotoxicity. Specifically, it has been found that ketamine treated neurons are more susceptible to damage as a result endogenous glutamate release. This increased susceptibility is due to recruitment of more NMDA receptors following prolonged blockade. When activated this increased number of receptors lead to calcium overload by exceeding the buffer capacity of mitochondria and interfering with the electron transport chain resulting in production of ROS C. .Ketamine and other members of the PCP-derivative family have a long history of drug abuse, especially by street drug users. Ketamine has even earned the street name of “Special K” due to its widespread use. Ketamine abusers are ultimately targeting the dissociative and hallucinogenic effects of the drug which are described as euphoric even in ketamine naïve subjects .The mechanism behind this addiction potential is believed to be a hijacking of the brains dopamine-based reward system. Subanesthetic doses of ketamine acutely increased extracellular concentration of dopamine in rat striatum and prefrontal cortex. Some human PET imaging also suggests that this occurs in humans. This mechanism that mimics the brain’s reward system associated with addiction in other pharmaceuticals .While therapeutic doses are generally less than street-use doses, several studies detailed below detail that even when used medically ketamine maintains addictive potential. When healthy ketamine-naïve subjects were infused with subanesthetic doses of ketamine they reported “liking” the feeling induced by ketamine and wanting more doses. In a group receiving higher doses of ketamine these cravings were relatively reduced while those on the lower dose infusions reported increasing desire for more of the drug .Another example of ketamine’s addictive potential comes from a 50-year-old anesthesia nurse who was suffering from Major Depressive Disorder (MDD). The nurse initially began self-medicating with weekly IM injections of ketamine. After weeks of self-medication, the patient began to develop significant tolerance to ketamine and had to stepwise increase both dose and frequency of the ketamine. Along with tolerance, the patient also developed significant ketamine addiction. When ketamine was stopped, patient began suffering intense craving and depressive episodes .While the research on ketamine’s addictive potential when used medically is somewhat limited, it should not be overlooked and both physicians and patients should be aware of and discuss this potential before adoption of ketamine-based therapies.While ketamine has been available for half a century, it has not been widely used in the medical community for decades. This has led to limited recent literature on its use, especially as an analgesic. Much of the information available on the use of ketamine for chronic pain relief is within case reports/series with relatively small sample sizes.Unfortunately, these limited numbers provide us with limited power to determine the true efficacy of ketamine in chronic pain conditions. This may be further exacerbated by publication bias in favor of publishing reports in which ketamine is effective. Reliance on case reports also leads to the possibility of treatment effect as almost none of these reports make use of placebo or non-active controls. These shortfalls make it evident that more large-scale placebo controlled clinical trials are necessary before being able to make a statistically strong conclusion on ketamine as a long-term analgesic.Another concern in some of the referenced studies is the possibility of confounding variables due to the large number of medications/treatments patients are often placed on prior to initiating ketamine therapy. Ketamine is currently used primarily as third-line analgesia and therefore patients are often on high-dose NSAIDs and opiates prior to trial of ketamine. This makes it hard to distinguish the singular effect of ketamine on pain relief, especially in the setting of opioid induced hyperalgesia.Research into the adverse event profile of ketamine has also been hampered by the infrequent use of the drug in monitored clinical settings. While the papers referenced in this article provide information on the short-term development of side effects, less is known about the long-term effect of ketamine treatment. Most of what we do know about the long-term development of problems such as ketamine cystitis and hepatotoxicity has been on subjects who used ketamine as a recreational street drug and at much higher doses than used for analgesia. This raises questions as to if patients treated medically with ketamine would experience the same appearance of these symptoms.In this article, we present ketamine as a therapy for cancer and chronic pain that is intractable to well-established therapeutics such as opioids. While ketamine has long been known as a dissociative anesthetic, its use as an analgesic agent in non-anesthetic doses is much more recent.Ketamine’s analgesic effects are believed to be an effect of NMDA-receptor blockade which decreases central neuronal excitability and therefore conduction of pain impulses. However, ketamine may also have other beneficial mechanisms of action when used to treat neuropathic pain such as the inhibition of microglial activation and neuronal inflammation as discussed above and demonstrated in several animal studies.Ketamine has repetitively been shown to reduce pain scores and subjective measures of pain. While the use of topical ketamine alone does not have strong supporting evidence, its use in multi-agent creams has been effective in some pain conditions.Use of ketamine has classically been associated with dissociative effects, however several recent studies have demonstrated that at sub-anesthetic dosages the occurrence of psychomimetic effects in the general population is minimal. Furthermore, the risk of these adverse events can be further reduced with pre-medication of benzodiazepines. A unique aspect of ketamine treatment in chronic pain patients is that it seems to counteract opioid-induce hyperalgesia and not therefore not only improves pain management but does so while simultaneously reducing a patient’s required total daily morphine equivalent. In some instances, this has been reported to improve quality of life while in others it serves to improve respiratory and hemodynamic stability.


The Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ) was created to evaluate specific treatment outcomes in terms of physical functioning, social ability, and mental health in patients with back pain-related diseases. In this study, we investigated whether the JOABPEQ could be used to construct a regression model to quantify low back pain and lower limb symptoms in patients with lumbar disc herniation (LDH). We reviewed 114 patients with LDH scheduled to undergo surgery at our hospital. We measured the degrees of 1) lower back pain, 2) lower limb pain, and 3) lower limb numbness using the visual analog scale before the surgery. All answers and physical function data were subjected to partial least squares regression analysis. The degrees of lower back and lower limb pain could be used as a regression model from the JOABPEQ and had a significant causal relationship with them. However, the degree of lower limb numbness could not be used for the same. Based on our results, the questions of the JOABPEQ can be used to multilaterally understand the degree of lower back pain and lower limb pain in patients with LDH. However, the degree of lower limb numbness has no causal relationship, so actual measurement is essential. Lower back pain leads to physical function and pathology problems and impairs activities of daily living (ADL) and causes psychological problems . Also, gIn recent years, the importance of evidence-based medicine has been emphasized, and various evaluation criteria require quantitative data regarding physical functions. It has been reported that low back pain treatment requires physiotherapy to improve function and willingness and adaptability to fight the disease on the part of patients and empathize on the part of the physician , 3. LoweDuring clinical practice, we often observe different degrees of pain reported by patients. Some patients may be highly tolerant to pain, even though their conditions are so painful that they cannot walk comfortably, whereas others may not be so tolerant. Thus, pain assessment depends on the patient's subjective pain complaints, regardless of physical function.The Japanese Society of Orthopedic Surgery created the Japan Orthopedic Association Low Back Pain Assessment Questionnaire (JOABPEQ) in 2007 from this perspective.The JOABPEQ combines the low back pain-specific quality of life (QOL) scale of the Roland–Morris disability questionnaire (RDQ) and the comprehensive health index of the Short-Form 36 Health Survey (SF-36) , reducedEach JOABPEQ domain is calculated with a value range of 0–100 points, with higher values being better . This trPrevious studies on the JOABPEQ used it before and after the intervention to evaluate the effects of treatments such as lumbar spine surgery and physical therapy. A study using correlation analysis reported that the degree of back pain correlates with the pain, walking function, and social life domains of the JOABPEQ. Therefore, studies using the JOABPEQ focus primarily on comparative testing and correlation analysis for the degree of back pain , 6. HoweThe study analyzed the data of 114 patients with lumbar disc herniation (LDH) scheduled for surgery at Funabashi Orthopedic Hospital. Then, we collected data on their answers to the JOABPEQ and lower back pain and lower limb symptoms and identified questions that could significantly affect the degree of lower back pain and lower limb symptoms. In this study, as a retrospective study, we investigated whether lower limb symptoms in patients with LDH scheduled for surgery at Funabashi Orthopedic Hospital correlated with the JOABPEQ responses. We then examined whether a regression model showing the degree of low back pain and lower limb symptoms could be constructed from the answers from the JOABPEQ in patients with LDH.Between August 2015 and August 2017, 213 patients diagnosed with LDH at the Funabashi Orthopedic Hospital were included in the study. They did not see any improvement in their symptoms with conservative therapy and planned to undergo excision. Patients with lumbar spinal stenosis, lumbar spondylolisthesis, lumbar scoliosis, or a history of lumbar spine surgery were excluded. The JOABPEQ was distributed and collected, and 99 patients who had one or more blanks in the JOABPEQ questionnaire were excluded from the study. The remaining 114 patients  were analyzed.Two trained physiotherapists performed the measurements. For pain evaluation, the degrees of lower back pain, lower limb pain, and lower limb numbness were measured using the visual analog scale (VAS) . For eacAll subjects consented and signed oral and written explanations of the purpose, method, and result's handling in this study. This study was also performed with the approval of the Ethics Committee of Funabashi Orthopedic Hospital .2 value), and correlation coefficient  between the predicted value and the measured value were calculated by PLS regression analysis. Also, the objective variables with predictive relevance were examined using the coefficients of each item of the JOABPEQ. The closer the Q2 value is to one, the higher the predictability of the model. The correlation coefficient (R) is a real value between -1 and +1. A positive R-value indicates a positive correlation, a negative R-value indicates a negative correlation, and a zero R-value indicates no correlation. Answers to the JOABPEQ questions were digitized using an ordinal scale. The Q2 value is defined by Formula 1. Also, “yobs” and “ycalc” indicate the PLS's measured values and calculated values, respectively.In this study, partial least squares (PLS) regression analysis  was perf2 value of zero or more. Regarding the objective variables with causal relationships, we focused on the absolute value of each question's coefficient in the JOABPEQ and examined the interrelationship with the objective variables. For statistical analysis, R (version 3.6.2) [Chin et al.  reportedn 3.6.2)  was usedFormula 2 of the linear model. The 114 subjects were patients who visited the Funabashi Orthopedic Hospital and did not select particular subjects.The PLS method is a multiple regression analysis using the least-squares method between the principal components calculated from the explanatory variables and the objective variable. The effectiveness of its use in healthcare data analysis has been demonstrated . A simplIn this study, the average value of each domain of the JOABPEQ was 31.8 points for pain-related disorders, 44.4 points for lumbar dysfunction, 35.1 points for gait dysfunction, 31.2 points for social life disorders, and 42.9 points for psychological disorders.2 value), and correlation coefficient , as determined by the PLS regression analysis.2 = 0.144, R = 0.292; the degree of lower limb pain had an average value of 66.75 mm, Q2 = 0.256, R = 0.358; and the degree of lower limb numbness had an average value of 59.53 mm, Q2 = -0.032, and R = 0.189.According to the results of the PLS regression analysis, the degree of lower back pain had an average value of 54.60 mm, QThe coefficient values of each item of the JOABPEQ in each objective variable are described below.The degree of lower back pain could be used as a regression model from the answers to the JOABPEQ and had a significant causal relationship with them (Q2 = 0.144). The correlation coefficient between the predicted and measured values showed a weak positive correlation (R = 0.292). Concerning the coefficient of each item of the JOABPEQ, those of pain-related, lumbar function, health, and psychological disorder were high .The items with high absolute values of the coefficients shown in 2 = 0.256). The correlation coefficient between the predicted and measured values showed a weak positive correlation (R = 0.358). Regarding the coefficient of each item of the JOABPEQ, those of social life, health, and psychological disorder were high .The degree of lower limb numbness could not be used as a regression model from the answers to the JOABPEQ and did not have a causal relationship with them , social activities, and well-being  owing to pain in the lower back and leg. Numbness may be experienced as a loss of sensation or a cold, icy feeling in one or more leg areas. Because there are several reasons for numbness, the predictor contains similar variants to obtain the coefficients.Furthermore, Affleck et al.  stated tA data mining method using multivariate analysis has the advantage of quantitative expression for clinical interpretation. With this extension, we believe that the patient's more detailed health status can be estimated by natural language analysis (text mining) of the contents of the chart itself. It is also easy to compare with standard physical functions and detect abnormalities. Based on the time series data, we can predict post-surgery conditions and prevent dysfunctions. In a study examining predictive models, Rowena et al.  reportedAs a clinical application, a combination of the subjective VAS, interviews, and high scores of the JOABPEQ for lower back pain and lower limb pain in LDH patients can predict the degree of lower back pain and lower limb symptoms. Specifically, it is necessary to check whether the patient can turn over in bed or stand up from a chair (Q2-3 and Q2-4), depending on their health condition. Physiotherapists can then suggest treatments based on questionnaires. For example, if LDH patients cannot turn over in bed, bedside physical therapy is recommended. If the patients can turn over in bed but cannot stand up from a chair, physical therapy in the sitting position is recommended. If they can turn over in bed and stand up from a chair, physical therapy in the standing position is recommended. Finally, physicians should consider patient health conditions when implementing physical therapy programs on specific days. We propose an informative description tree of treatment guidelines for physical therapy in patients with LDH . For exaThis study's limitation is that the subjects were cases of LDH scheduled for surgery, and cases that could be treated with conservative therapy were not included. Also, the sub-analysis of disease duration, vertebral body level, and hamstring tension was not performed. As future prospects, we will compare the JOABPEQ scores between patients who chose to undergo LDH surgery and those with LDH who did not eventually undergo surgery. Perhaps patients with LDH who require surgery will have a specific response that correlates more strongly than patients with LDH who do not require surgery.In this study, we examined whether a regression model can be constructed from the JOABPEQ questions regarding the degree of low back pain and leg pain. Therefore, the degree of low back pain and leg pain correlated with the response to the JOABPEQ, and a regression model could be used.As a clinical application of LDH patients, by checking the movement of turning over in bed and getting up from a chair, the degree of low back pain and lower limb symptoms can be quantified, contributing to the evaluation of physical therapy and the planning of treatment programs.S1 Data(XLSX)Click here for additional data file.


Equal numbers of males and females present with chest pain to tertiary hospital EDs, but men are twice as likely to get ICA. Over one-third of ICAs occur in those with normal troponin levels, indicating that further investigation is required to determine risk profile, outcomes and cost effectiveness.We investigated patients presenting to emergency departments (EDs) with chest pain to identify factors that influence the use of invasive coronary angiography (ICA). Using linked ED, hospitalisations, death and cardiac biomarker data, we identified people aged 20 years and over who presented with chest pain to tertiary public hospital EDs in Western Australia from 1 January 2016 to 31 March 2017 (ED chest pain cohort). We report patient characteristics, ED discharge diagnosis, pathways to ICA, ICA within 90 days, troponin test results, and gender differences. Associations were examined with the Pearson Chi-squared test and multivariate logistic regression. There were 16,974 people in the ED chest pain cohort, with a mean age of 55.6 years and 50.7% males, accounting for 20,131 ED presentations. Acute coronary syndrome was the ED discharge diagnosis in 10.4% of presentations. ED pathways were: discharged home (57.5%); hospitalisation (41.7%); interhospital transfer (0.4%); and died in ED (0.03%)/inpatients (0.3%). There were 1546 (9.1%) ICAs performed within 90 days of the first ED chest pain visit, of which 59 visits (3.8%) had no troponin tests and 565 visits (36.6%) had normal troponin. ICAs were performed in more men than women (12.3% vs. 6.1%,  Chest pain is one of the most common presenting conditions to emergency departments (EDs) worldwide, with over 6.5 million presentations per year in the USA . In AustThe risk of ACS in patients presenting with chest pain is assessed through symptoms and cardiovascular risk factors, serial electrocardiographs (ECGs) and biomarkers of myocardial injury . In partThe aim of our study was to describe the patient characteristics, ED discharge diagnosis, determinants and use of ICA following ED presentations for chest pain in Western Australia (WA) in the period 2016–2017. Our motivation was to understand patient profiles and the scenarios by which patients are admitted for ICA given the increasing ED presentations for chest pain in Australia , and incStudy datasets of linked administrative records were obtained from the Western Australian Department of Health consisting of hospital morbidity data (inpatient admissions), ED visits and death registrations. These are core datasets of the Western Australian Data Linkage System in which records belonging to the same person are linked using a dynamic probabilistic matching algorithm . Our stuThe ED chest pain cohort was also linked to troponin results from Pathwest Laboratory Medicine that provides pathology services to the tertiary hospitals. Our ED dataset did not have the ED discharge date and time. Hence, linkage of troponin data was based on the period from (ED presentation time—1 h) to (ED presentation time + 6 h) to capture all cardiac biomarker tests where blood samples were collected within 1 h prior to the ED admission time and up to 6 h after the ED admission time. Troponin test results were classified as normal or elevated based on the gender-specific assay threshold for the laboratory, then further classified as all tests normal, all tests elevated or at least one test elevated with results showing a rising or falling pattern . The troStudy approval was received from the Western Australian Department of Health Human Research Ethics Committee and Research Governance Office (RGS 2876), and the Human Research Ethics Committee of The University of WA (RA/4/1/7230).Patients in the ED chest pain cohort were grouped into the following ED discharge categories based on ICD-10-AM  codes frCoronary angiograms can be performed following any of the ED discharge pathways (except if died in ED), including repeat angiograms after an initial procedure. We used the linked hospital admissions data to identify ICAs from any of the procedure fields within 90 days following ED discharge pathways 1, 3 and 4. This included the initial and any repeat angiogram procedures within 90 days of a visit to the ED for chest pain. If hospital admission records following the ED presentation had a coronary artery revascularisation procedure (percutaneous coronary intervention or coronary artery bypass graft surgery) coded, but no procedure codes for coronary angiography, then we assumed that angiography was performed and not coded. In this case, the assumed angiography was counted together with angiogram procedures that were coded in the hospital admissions data. This allowed a more complete identification of ICA following the ED presentation. Coronary computed tomography angiography (CCTA) is a non-invasive modality with an emerging role in the investigation of chest pain as an alternative to ICA, especially in low-risk patients ,13. HoweA flowchart was constructed showing the five ED discharge pathways for the ED chest pain cohort, with counts and proportions representing the number of visits to ED or hospital inpatient admission. Frequencies were reported for the number of ICAs and the ED discharge diagnosis of the cohort. For visits that resulted in an inpatient admission (pathways 2 and 3), a bivariate analysis of ED discharge diagnosis and principal discharge diagnosis of the corresponding inpatient admission revealed how the diagnoses changed from ED to inpatient. We used the 2-sided Pearson Chi-squared statistic or Fisher’s exact test to test for associations between troponin test results, sex, age group, and remoteness area and use of ICA within 90 days of the ED presentation. Differences between men and women were compared for age, remoteness area, ED discharge diagnosis, 10-year comorbidity history, troponin test results and initiation of ICA. These were assessed from the first ED presentation for chest pain for each person in the ED chest pain cohort for a person-based analysis. A multivariate logistic regression model was used to further investigate any gender differences by estimating the odds of initiating ICA in men compared with women (as reference level) adjusting for age (continuous variable), remoteness area, ED discharge diagnosis and troponin test results.Additional stratified analyses assessed the use of angiograms within 90 days from the first ED chest pain presentation compared with use beyond 90 days (to 30 June 2017). Residential remoteness was assessed by remoteness areas which divide Australia into 5 classes of remoteness based on the Accessibility and Remoteness Index of Australia (ARIA+) using Statistical Area Level 2 (SA2) from the 2011 census (2016 SA2 data were not yet available) . For theCharacteristics of the ED chest pain cohort are shown in The majority of ED visits for chest pain resulted in an ED discharge diagnosis of chest pain 47.9%, , with non = 11,568 visits, 57.5%) and non-fatal hospital inpatient admission  respectively. Together, these make up 99.2% of the ED discharge pathways in the ED chest pain cohort. A small proportion of the cohort died following inpatient admission from ED  or in ED during the initial visit . Pathway 4 was transfer to another tertiary hospital ED then discharge home without inpatient admission . Pathways 1, 3 and 4 led to ICA  of ED visits had a troponin I test(s) completed. Patients who had an ED discharge diagnosis of MI or other coronary heart disease were those with the highest proportion of elevated troponin I test results (High-sensitivity troponin I was the exclusive cardiac biomarker test completed in the ED chest pain cohort . However results . Patientp < 0.0001). There were 59 (3.8%) initial angiograms in which no troponin test results were recorded. Patients with elevated troponin I test results were more likely to have an initial angiogram within 7 days of the ED presentation (94% completed in the first 7 days). There were 565 (36.6%) initial angiograms completed in patients who had all troponin test results normal. Patients who had angiograms following normal troponin levels had a high prevalence of coronary heart disease .Coronary artery revascularisation procedures were identified in 1064 (6.3%) patients following the ED presentation, with 925 (86.9%) of these having the procedure within 90 days of the ED presentation. There was a significant association between time to first revascularisation procedure and troponin test results. Of the 1064 patients, revascularisation procedures within 90 days were done in 25 (68%) of those with no troponin tests, 266 patients (74%) who had normal troponin tests and 634 (95%) who had at least one elevated troponin result  or remoteness area (p = 0.45) within 90 days of the first ED chest pain presentation . However, there was no difference in the timing of the coronary angiogram, with 84% of procedures initiated in the first 7 days in both men and women. Patients in the cohort who had two or more ED chest pain presentations had some differences in characteristics to the total cohort, reflected as older age and a higher prevalence of comorbidities. This subgroup would require further study and assessment of the costs associated with their additional use of healthcare resources.Approximately half of the chest pain visits had an ED discharge diagnosis of non-specific chest pain, and a further 30% were diagnosed with non-cardiovascular conditions. Hence, only approximately 20% of chest pain visits had a cardiovascular diagnosis on discharge from ED. ACS as an ED discharge diagnosis was identified in 10.4% of presentations to the EDs for chest pain (12.3% in men and 7.6% in women). Whilst this important measure is not reported in Australian national statistics on ED care, Cullen et al. found a similar proportion of 11% for ACS as an ED discharge diagnosis in their single-centre study of ED chest pain presentations in Australia from 2008 to 2011 . In the Pathways to coronary angiography mostly involved discharge home from ED with subsequent admission for angiography or direct admission to hospital inpatients with/without immediate angiography and discharge home with/without subsequent admission for initial or additional coronary angiography. This reflects the patient casemix where the lower-risk patients  may not require immediate ICA, whilst the smaller group of patients with an ED diagnosis of ACS would require more urgent diagnostic and therapeutic attention. There also appeared to be consideration of specific patient circumstances. For example, ICA in patients residing in remote or very remote locations were more likely to be done within 7 days of the ED chest pain visit than for patients living in major cities. This may reflect a patient convenience and elucidation of the presenting complaint by initiating the procedure whilst they are in the tertiary hospital rather than discharging them home with a subsequent admission for an elective angiography (pathway 1). This may be more clinically and cost effective in large jurisdictions as in Australia where ICA services are located mostly in major cities, with patients from rural and remote areas having to travel long distances to receive these procedures.n = 59) of ICA within 90 days of the ED visit were from visits with no troponin tests. Approximately half of the patients (n = 25) with no troponin tests had a coronary artery revascularisation procedure within 90 days of the ED visit. This may partially explain the use of ICA in those with no troponin tests, but we were not able to determine other reasons in this group of patients. Whilst high-sensitivity troponin was thought to aid in the precision of diagnosing ACS [Whilst the majority of ICAs performed was in patients with elevated troponin levels, 37% were completed in patients with normal troponin levels. Almost half of these patients had a history of coronary heart disease, and angiography may have been initiated for evidence of disease progression despite the normal troponin. The clinical and cost implications of this requires further investigation. In addition, 27.8% of chest pain visits did not have any troponin tests recorded in the linked pathology data. The majority of these patients had a non-coronary heart disease diagnosis on ED discharge. However, 4% . The variation was only in frequency rather than timing of the procedure following the ED chest pain visit. Men were significantly younger, were less often from major cities, were more likely to have an ED discharge diagnosis of ACS, had a higher prevalence of hospitalised comorbidities  and were more likely to have troponin tests and elevated troponin test results. These observations indicate that they may have been considered higher risk than women, and future analyses of outcomes of the ED chest pain cohort will investigate this. Variations in coronary angiogram rates have been observed in Australia, but not related to clinical need although there is a modest positive correlation between ICA rates and ACS rates .The strength of our study was the use of contemporary population-based linked administrative data covering ED presentations, hospital inpatient admissions and death. This allowed identification of chest pain presentations at multiple tertiary ED sites with complete follow up of patients to determine frequency and timing of ICA in any coronary angiography capable sites. There was also complete capture of all-cause death, both in-hospital and out-of-hospital deaths. The hospital inpatient admissions data covered both private and public hospitals throughout the state, so all admissions to hospital following the ED presentation would have been captured. Linkage to cardiac biomarker data allowed an additional level of interpretation of findings based on troponin testing which is part of the diagnostic pathway in managing presentations to ED for chest pain.The ED data did not include discharge date and time, so biomarker records from the hospital inpatient admission may have incorrectly linked to the ED visit. To account for this, we limited the linkage window to 1 h before and 6 h after the ED presentation time to minimise the number of hospital biomarker tests that would have linked to the ED visit. Hence, ED visits longer than 6 h would not have linked any biomarker tests from blood collected after 6 h in ED. However, this would have minimally affected the number of high-sensitivity troponin tests that were associated with the ED visit because serial testing of high-sensitivity troponin is separated by 2–3 h ,16. It iWe did not have any ECG data or symptoms for the ED chest pain presentations, and relied on the diagnosis made by attending clinicians at the time of the presentation in each tertiary site. This was recorded in the administrative ED dataset from the clinical diagnosis made by doctors based on all diagnostic information available during the ED visit. Tertiary EDs have standard clinical guidelines on the management and diagnosis of chest pain, ACS and other coronary heart disease and this is based on high-sensitivity troponin, not just ECGs. The ECG is used to identify the presence of ST elevation which determines the type of initial treatment required . In this study, we were interested in diagnostic ICA rather than treatment, and so the troponin tests were of greater importance. Some patients had coronary artery revascularisation procedures following their ED chest pain visit, but no ICA. For these, we assumed that an angiogram was performed but not coded because revascularisation procedures cannot be performed without imaging details that show the location and extent of stenosis in the coronary arteries. Cardiologists and surgeons require this information prior to attempting any revascularisation procedure, whether it is percutaneous coronary intervention or coronary artery bypass surgery. It is possible that instead of ICA some patients may have had CCTA outside of the hospital sector , and these would not be captured through the inpatient admissions data.Only one in five ED presentations for chest pain are discharged from ED with a diagnosis of cardiovascular disease, with 10.4% diagnosed with ACS. Men and women are equally represented in ED chest pain visits, but have significantly different demographic and clinical characteristics. This may have influenced the frequency of use of ICA between men and women following ED discharge, but the timing was the same, with 84% of angiograms initiated in the first 7 days for men and women. The most common pathways to initiation of angiograms were direct admission to hospital with/without immediate procedure and discharge home with subsequent procedure within 90 days. Subsequent investigation of ED chest pain presentations will reveal cost effectiveness and outcomes for the various pathways to ICA, especially in patients with contiguous presentations to ED for chest pain.


Thoracic epidural anesthesia is no longer considered the gold standard for perioperative analgesia in laparoscopic colorectal procedures. In the search for alternatives, the efficacy of the transverse abdominal plane (TAP) block and other abdominal wall blocks such as the transmuscular quadratus lumborum (TQL) block continues to be investigated for postoperative pain management. Most of the initial studies on TAP blocks reported positive effects; however, the amount of studies with negative outcomes is increasing, most probably due to the fact that the majority of abdominal wall blocks fail to mitigate visceral pain.The TQL block could prove attractive in the search for better postoperative pain relief after laparoscopic colorectal surgery. In several cadaveric studies of the TQL, a spread of dye into the thoracic paravertebral space, the intercostal spaces, and even the thoracic sympathetic trunk was reported.Given the advantage of possibly reaching the thoracic paravertebral space, the potential to reach nerves transmitting visceral pain, and the possible coverage of dermatomes T4–L1, we hypothesize that the TQL provides superior postoperative analgesia for laparoscopic colorectal surgery as compared to patient-controlled intravenous analgesia with morphine alone.n = 75), or a bilateral TQL block with 30 ml saline each on both sides plus postoperative patient-controlled intravenous analgesia with morphine . Our primary outcome parameter will be the morphine consumption during the first 24 h postsurgery. Secondary endpoints include pain intensity as assessed with the numerical rating scale (NRS) for pain, time to return of intestinal function (defined as the time to first flatus and the time to the first postoperative intake of solid food), time to first mobilization, the incidence of postoperative nausea and vomiting during the first 24 h, length of stay on the post anesthesia care unit (PACU) and in the hospital, the extent of sensory block at two time points (admission to and discharge from the PACU), the doses of morphine IV as requested by the patient from the PCA pump, the total dosage of morphine administered IV, the need for and dose of rescue analgesics , free plasma ropivacaine levels after induction and at discharge from the PACU, and the incidence of adverse events during treatment ).In this prospective, randomized, double-blind controlled clinical trial, 150 patients undergoing laparoscopic colorectal surgery will be included. Patients will be randomly allocated to two different analgesic strategies: a bilateral TQL with 30 ml ropivacaine 0.375% each on both sides, administered before induction of anesthesia, plus postoperative patient-controlled intravenous analgesia with morphine  are known to have an analgesic effect only on somatic pain. Recognizing the importance of procedure-specific pain management, we aim to investigate whether a transmuscular quadratus lumborum block delivers superior pain control in comparison to patient-controlled intravenous analgesia with morphine alone.2019-002304-40. Registered on 17 September 2019EudraCT identifier  Locoregional anesthesia has become a key element in multimodal analgesia .With the increasing acceptance of and evidence for enhanced recovery protocols, the use of regional anesthesia continues to broaden. While the use of thoracic epidural anesthesia cannot be considered the gold standard anymore in laparoscopic colorectal procedures, the efficacy of the transverse abdominal plane (TAP) block and other abdominal wall blocks remains to be established , 3. ThouWe think that the efficacy of these blocks has been waning in the last years primarily because of advancements in surgery. Increasing experience in laparoscopic surgery with low flow/low pressure pneumoperitoneum has probably decreased the severity of somatic wall pain . In contNotably, visceral pain stimuli are transmitted via the ventral branches of the spinal nerves. Therefore, the TQL block  could prove beneficial in the search for better postoperative outcomes .With this block, a spread of local anesthetics is achieved between the psoas major (PM) muscle and the quadratus lumborum (QL) muscle. Controversy on the exact anatomy remains. Some claim the anterior thoracolumbar fascia is the main target at that site. Most likely, the fascial interspace posterior to the transversalis fascia between PM and QL is the real point of injection. There is no evidence of an anterior thoracolumbar fascia, and the posterior muscle groups like the erector spinae group  also have a different origin of embryonic development Fig. .Fig. 1TIn this compartment, the ventral rami of the spinal nerves pass by at the dorsal side of the quadratus lumborum muscle. Because TQL remains a fascial plane wall block and as such depends on an extensive spread of local anesthetics to be effective, this field block requires a relatively high volume of local anesthetics (20–30 ml) due to the distance between injection site and target area.The TQL has been shown to provide adequate analgesia in several smaller studies and case reports , 9. HoweThis study is a single-center, prospective, randomized, double-blind, controlled trial.The aim of this trial will be to investigate the efficacy of the TQL block on postoperative pain and enhanced recovery.The trial will be carried out in compliance with the principles of the Declaration of Helsinki, the principles of Good Clinical Practice, and following all regulatory requirements. The study is approved by the ethics committee of the University Hospitals Leuven on 17 September 2019 with the reference number S62905. B, the Clinical Trials Centre of the University Hospitals Leuven, and the “Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten.” The study is registered in the European Clinical Trials Database of the European Medicines Agency, EudraCT number: 2019-002304-40, 17 September 2019.Protocol amendments if needed will be re-sent to the ethical committee for revision. Any amendments will be made by the PI, and protocol changes accepted by the committee will be adjusted accordingly. Any breach of protocol during the recruitment and trial phase will be fully documented using a breach report form. Amendments will be added to clinical trial registries Fig. .Fig. 2FAll consecutive patients planned for elective laparoscopic colorectal surgery in an enhanced recovery program will be included in the trial after obtaining informed consent. Patients will be recruited in the Department of Abdominal Surgery of the University Hospitals of the KU Leuven, Belgium. Possible risks will be explained to the patients. Patients willing to participate in the study will get information bedside, and written informed consent will be obtained. Informed consent will be the responsibility of the principal investigator (PI) or the study nurse. According to the Good Clinical Practice guidelines, all information will be given to the patient and family either at the ward 1 day before surgery or during the preoperative counseling. Two informed consents will be signed by both parties. One is securely stored and labeled in the clinical research facility of the Department of Anaesthesiology UZ Leuven, Belgium. Patients will receive the second informed consent after recruitment. Recruitment can of course always be retracted before, during, or even after trial start and will have no influence on further treatment of patient.On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the Universities taking part in the research or from regulatory authorities, where relevant. This trial involves collecting biological specimens for storage. Storage of specimens will be anonymized, coded, and stored in the UZ Leuven Clinical Trials Centre. Secondary studies or analysis is not planned on biological specimens.There is no anticipated harm and compensation for trial participation. No provision for post-trial care is foreseen. Patients however have the benefit of a trial insurance protection against potential harm by the UZ Leuven, which is provided and stated in the informed consent.n = 75). Patients in the placebo group (P-group) will receive a bilateral TQL block with 30 ml saline 0.9% on both sides (placed before the induction of anesthesia) plus postoperative PCIA with morphine . Patients will be randomized using a computer-generated permuted block randomization sequence . Allocation concealment will be ensured by enclosing assignments in sealed, opaque, sequentially numbered envelopes which will be opened only upon arrival of the patient in the preparatory block rooms [Patients will be randomized to one of the 2 study groups. Patients in the TQL group will receive a bilateral TQL block with 30 ml ropivacaine 0.375% on both sides (placed before the induction of anesthesia) plus postoperative patient-controlled intravenous analgesia (PCIA) with morphine  age between 18 and 75 years, (2) patient scheduled for elective laparoscopic colorectal surgery, (3) American Society of Anesthesiologists classification of physical status < IV, (4) body mass index (BMI) ≤ 35, and (5) patient able to understand the use of intravenous patient-controlled anesthesia. The exclusion criteria are as follows: (1) refusal of the patient, (2) known hypersensitivity to any study medication, (3) chronic opioid use or chronic pain patient, (4) liver insufficiency , (5) renal insufficiency (defined as a glomerular filtration rate < 44 ml/min), (6) morbid obesity (defined as a BMI > 35), (7) obstructive sleep apnea syndrome, and (8) inability to operate a PCIA system.The ERAS (“Enhanced Recovery After Surgery”) protocol will be used in all patients in order to standardize perioperative treatment in both groups . The ERAIn general, management will be performed according to our institutional standards. It is, however, possible that the attending anesthesiologist changes this management to optimize the patients’ care.2 = 1.0), general anesthesia will be induced with a combination of an intravenous infusion of remifentanil (0.5 μg kg−1 min−1) followed by a bolus of propofol 0.5–1 mg kg−1. Tracheal intubation will be facilitated by a bolus administration of rocuronium 0.6 mg kg−1. Standard American Society of Anesthesiologists monitoring will be completed with temperature and capnography measurements. In addition, the bispectral index (BIS) will be used to standardize depth of anesthesia.Prior to anesthesia, patients must be in a fasting state for 6 h and no premedication is given. After application of a 5-lead electrocardiogram and pulse oximetry, a peripheral intravenous line (16-gauge cannula) and a radial arterial catheter (20-gauge) for the invasive measurement of arterial blood pressure will be placed. After preoxygenation (FiO−1 (max. 4 mg) intravenous dexamethasone at induction and 0.1 mg kg−1 (max. 4 mg) intravenous ondansetron 30 min before the end of surgery.Further curarization will be left upon the discretion of the attending anesthesiologist and according to the results of relaxometry. PONV prophylaxis will be achieved with 0.1 mg kg2 = 0.4–0.5), titrated to achieve a BIS of 40–60. Analgesia is achieved with a continuous infusion of remifentanil (0.1–0.3 μg kg−1 min−1) and adjusted depending on patients’ reactions, spontaneous movements, sweating, and/or sudden increase in heart rate or arterial pressure.General anesthesia will be maintained with sevoflurane 1.5–2.0% , the full vertebral body (VB), and the 3 important muscles making up the “shamrock” sign (the erector spinae muscle at the back (ESM), the QL muscle itself, and the psoas muscle (PM)) will be identified .The interfascial space between the QL muscle and the PM will be our main target. Aligning the probe more cephalad along the midaxillary line can improve visualization; however, the space between iliac crest and rib cage can be minimal. There are 3 possible approaches described thus far.All are transmuscular targeting the fascial interspace between psoas major and quadratus lumborum muscle: the classical posterior approach, the more cephalad subcostal approach, and the posteromedial approach . Depending on the patient’s anatomy, we will perform a classical posterior technique, only reverting to the TOP procedure if this improves visualization Fig. .Fig. 4UIdentifying the abdominal wall muscles anterior Identifying the so-called shamrock signClearly visualizing moving tissue to distinguish the fascia transversalis from the tissue interspace between psoas major and quadratus lumborum muscle (the two muscles do not move during respiration)Correct identification of the point of injection will follow a well-defined and recently published 3-step method :IdentifPatients in the placebo group will receive a bilateral placebo block bolus using 30 ml normal saline 0.9%.To achieve blinding of the patients and study observers, the trial medications have the same volume of 30 ml and are identically looking. Both the investigational medicinal product and placebo will be labeled with the mark “trial medication.”Irrespective of group allocation, postoperative analgesia will be provided by administering acetaminophen IV (15 mg/kg 4/day), ketorolac 10 mg IV (20 mg over 24 h), and a bolus of 0.1 mg/kg of morphine at the end of surgery. Following surgery, patients will receive a morphine IV PCA pump which will be programmed in an on-demand-only mode. The PCIA pump will be set at 1.5 mg every 7 min with a maximum of 30 mg every 4 h.Further analgesic treatment is dependent on the protocol used on the ward with intravenous acetaminophen (15 mg/kg 4/day) and tramadol-hydrochloride (50 mg 4/day) being used in a fixed scheme.The patients will be transferred to the PACU for continuous monitoring of vital signs and the Aldrete score. In the PACU, severity of pain will be assessed at rest and during coughing by a numeric rating scale (NRS) . In case of severe surgery-related pain despite the adequate use of the morphine IV PCA, an extra bolus of morphine can be given IV until adequate pain levels are reached (1–2 mg IV up to 0.1–0.2 mg/kg). In case of persistent pain, and NRS ≥ 3, rescue medication will be initiated. Ketamine will be the first drug of choice administered using boli of 0.1 mg/kg IV. In case of an insufficient effect and a persistent NRS ≥ 3, a bolus of clonidine 2 μg/kg can be given IV. Severity of pain will be monitored every 15 min during the first 2 h of the PACU stay and hourly during the remaining PACU stay.PONV will be treated with iv-dehydrobenzperidol 0.625 mg (PACU) or iv-ondansetron 4 mg (on the ward). Patients will stay at least 4 h in the PACU. Patients will be discharged from the PACU only once the Aldrete score is 9 and once there is no evidence for pain and/or PONV.Serum-free ropivacaine will be sampled at 1 h after injection and at 4 h postinjection.Storage of specimens will be anonymized, coded, and stored in the UZ Leuven Clinical Trials Centre. Secondary studies or analysis is not planned on biological specimens. All samples will be analyzed in batch at the conclusion of the trial. Storage is provided in a secured clinical trial deep-freeze facility  at strict temperature control of -80 degrees Celcius. Quantitative Mass Spectrometric Analysis (QMAs) of ropivacaine on all serum samples will be performed by a specialized and highly experienced laboratory affiliated to the UZ Leuven. All samples are transported and remain coded and anonymized. The aforementioned laboratory is independent, has no other involvement, and is not a stakeholder in the study.Patients will be visited once daily throughout their hospital stay by research personnel.Twenty-four hours after surgery, the morphine IV PCA system will be removed and data will be extracted .As the primary outcome parameter, we will evaluate the cumulative morphine consumption in the first 24 postoperative hours.The secondary outcome parameters include following: (1) pain intensity as assessed with the numerical rating score (NRS) for pain, (2) time to first mobilization, (3) the incidence of postoperative nausea and vomiting during the first 24 h, (4) length of stay on the PACU and in the hospital, (5) extent of sensory block at two time points, (6) number of morphine boli as requested by the patient from the PCIA system, (7) total dosage of morphine IV delivered, and (8) the need for and dose of rescue analgesia .Safety endpoints measured will include the incidence of (serious) adverse events, the occurrence of signs of local anesthetic systemic toxicity (LAST), and the plasma levels of free ropivacaine.The study medication will be administered to patients with standard hemodynamic monitoring in the setting of a fully equipped operation theater. The administration of the trial medication will be stopped immediately in case that the patient shows any adverse event during the procedure. Also after leaving the operation theater, all patients will still be meticulously monitored for the appearance of eventual (severe) adverse events, first on the PACU, later on the surgical ward. In addition, the inclusion of each individual patient into the trial is denoted in the electronic hospital information system and hence visible to all physicians and nurses involved in the care of this patient. All adverse events will be reported immediately to the research coordinator and principle investigator. The principal investigator will report suspected unexpected serious adverse reactions to the federal health authorities.https://www.cytel.com/software/east).The coefficient of variation (CV) in postoperative morphine consumption was assumed to equal 0.7 and derived from own data as reported by Dewinter et al. To have 80% power to show a 30% reduction of the 24-h consumption in the ropi group versus the placebo group using a two-sided test for a ratio of means , at least 51 patients per group are needed . One interim analysis for futility is planned after accrual of 50% of the participants. To preserve the desired power level, 106 subjects in total are required, based on the O’Brien-Fleming-type error spending function and applying a non-binding boundary to have the flexibility to continue the trial when the test statistic falls in the acceptance region at the interim analysis . The totU test will be used to test the robustness of the conclusion if the log-transformed data showed a departure from normality based on the Shapiro-Wilk W test statistic. As a secondary analysis, the same approach will be applied in the subgroup of patients with a BMI ≤ 30. As a further exploratory analysis, it will be verified if the effect of ropivacaine depends on BMI by adding the interaction between group and BMI into the model .For the primary outcome, a two-sided test for the ratio of means will be used to compare the 24-h cumulative morphine intake between both groups. The test will be based on a linear model on log-transformed values with group and the stratification variable (BMI ≤ 25) as factor. A 95% confidence interval for the ratio (of the geometric means) will be reported. A stratified Mann-Whitney Z-statistic ≤ 0.55 . This corresponds to a conditional power (to show a difference) equal to 0.047 and 0.427 when the remaining data are sampled from a population defined by the parameters under the null and the alternative hypothesis, respectively.After inclusion of 50% of the subjects, a non-binding interim analysis will be performed based on the O’Brien-Fleming-type error spending function, accepting the null hypothesis when the U tests will be used when the data is measured on a ratio or ordinal level. A linear model for longitudinal measurements (with the selection of the covariance structure based on the Akaike Information Criterion) will be used for variables that are measured over time (NRS for pain). The number of times morphine IV PCA is requested will be analyzed using a model for count data . Incidence of local anesthetic systemic toxicity (LAST) will be compared using Fisher’s exact test. A Mann-Whitney U test will be used for the maximum number of dermatomes, separately at two time points (after the first and after the last dose). The postoperative evolution of the incidence of nausea and vomiting will be evaluated with a logistic regression model with generalized estimating equations (GEE). Fisher’s exact test will be used for the comparison of the presence of “ever PONV” during the postoperative follow-up, as well as for each of the early safety endpoints at 30 days (serious adverse events).Secondary outcomes will be compared using Fisher’s exact test in case of proportion measurements, and Mann-Whitney p value smaller than 0.05 will be considered significant.All analyses will be based on the intention-to-treat (ITT) principle, and a Analyses will be performed using SAS software, version 9.4 of the SAS System for Windows.A co-investigator or a study nurse will review completed case record forms for completeness and correctness before digitalization and statistical analysis. Case record forms will be completed from data drawn from the source documents and the electronic hospital information system. Missing data is not expected as all clinical data are mandatorily collected in the electronic hospital information system. Data will be coded and analyzed in line with the intention-to-treat principle.Local regional anesthesia plays an important role in multimodal pain management. In the last decade, abdominal wall blocks such as the TAP block have been shown to be efficient in the control of postoperative pain in patients undergoing laparoscopic colorectal surgery –19. HoweUntil now, the most effective analgesic strategy in these patients especially in an enhanced recovery program is still unknown. Recognizing the importance of procedure-specific pain management, we aim to investigate whether a TQL block delivers superior pain control in comparison to PCIA with morphine alone.The interventional treatment will be performed under hemodynamic monitoring in a fully equipped preoperative block room. Risk of local anesthetic systemic toxicity will be minimized by ultrasound guidance and needle aspiration before injection . PatientThe TQL block has been shown to be safe in numerous reports. Large doses of local anesthetics carry the potential risk of local anesthetic systemic toxicity and can affect the cardiovascular system and central nervous system . As a saAlso, the inclusion of each patient into the trail is denoted in the electronic hospital information system. Hence, this is visible to all physicians and nurses involved in the patients’ care. All adverse events will be reported immediately to the research coordinator and principal investigator. The latter will report suspected unexpected serious adverse event to the federal health.There is no guarantee that the use of TQL block with local anesthetic ropivacaine will provide a benefit to the participating patient.Patient recruitment will start in October 2019. The predicted study completion date is December 2020. Protocol version SC 05 – 19-07-2019.


Pulsed radiofrequency (PRF) of the suprascapular nerve has been shown to be effective in the treatment of chronic shoulder pain. Ultrasound (US) guidance has gained popularity in regional blocks recently. This study aims to investigate the efficacy of suprascapular nerve pulsed radiofrequency under the guidance of ultrasonography.This retrospective study included patients treated with PRF of the suprascapular nerve with a diagnosis of partial rotator cuff tears. The patients were assessed with a numeric rating scale (NRS), the Shoulder Pain and Disability Index (SPADI), and a Likert patient satisfaction score before the treatment and 3 weeks and 6 months following the treatment.A total of 31 patients was included in the study. The patients’ mean age was 66.8 ± 13.3 years. The mean scores of the NRS,SPADI, and Likert scale before the procedure  and at 3 weeks  and 6months  after the procedure were evaluated. We observed significant improvement in NRS, SPADI, andLikert scores at 3 weeks and 6 months following the treatment (P < 0.001).The study demonstrated that US-guided suprascapular nerve PRF achieves good pain relief and functional improvementin patients with partial rotator cuff tears for at least 6 months. Management of shoulder pain requires a multimodal andalgorithmic approach, including the use of nonsteroidalantiinflammatory drugs (NSAIDs), physiotherapy,selective nerve interventions, and surgical procedures [1].Generally, a suprascapular nerve block is administeredfirst with local anesthetic agents and corticosteroids [2].The technique is often useful only for the short term,and repeated interventions are needed. Thus, the risk ofnerve injury, infection, and side effects due to steroid usemay increase [3]. Other therapeutic options, includingneurolysis or neurectomy of the suprascapular nerve,may cause permanent paralysis of the supraspinatus andinfraspinatus muscles [4].Suprascapular nerve pulsed radiofrequency (PRF)neuromodulation has emerged as an alternativeintervention for pain control since 2002 and has beenincreasingly used to date [5]. Recent studies have reportedthat suprascapular nerve PRF under ultrasound (US)guidance provides direct visualization of the nerve,thereby allowing the more rapid onset of anesthesia .The main advantage of US-guided suprascapular nervePRF over other pain management methods is that a singleapplication provides long-term pain relief with a lowerincidence of neural trauma . However, there arelimited studies evaluating the usefulness of the procedurein partial rotator cuff tears under US guidance [10].In this study, we aimed to investigate the efficacy of USguidedsuprascapular nerve PRF on chronic shoulder painand function in patients with partial rotator cuff lesions.This retrospective study included 31 patients  who underwent US-guided suprascapular nervePRF between May 2016 and November 2018 and who hadshoulder pain for at least 3 months due to partial rotatorcuff tear. Written informed consent was obtained fromeach patient. Patients’ data were obtained from patientfiles and follow-up forms. The institutional review board approved the study protocol , and thestudy was conducted according to the principles of theDeclaration of Helsinki.The inclusion criteria for the study were as follows:refractory shoulder pain unresponsive to conservativetherapies including paracetamol, NSAIDs, opioids,physiotherapy, intraarticular steroid injections, orcombinations of these treatments, and radiologicallyproven partial tear of the rotator cuff.Exclusion criteria included inflammatory arthritis,adhesive capsulitis, active synovitis of the shoulder joint,previous history of shoulder surgery, shoulder jointinjection in the last 1 month, advanced osteoarthritis,neurologic conditions , current use of anticoagulant medications, andpresence of complete tear of the rotator cuff.All patients underwent shoulder radiography before thetreatment, and the etiology of a partial tear of the rotatorcuff was documented by magnetic resonance imaging(MRI) findings. A radiologist evaluated the MRIs of thepatients. MRI revealed muscle atrophy in 6 (19%) patients;nevertheless, the volume of muscle was larger than that of fat(muscle > fat). On the other hand, average muscle volumewas observed in the remaining 25 (81%) patients. Humeralhead migration and cysts were not observed in any patient.Patients were evaluated using a numeric rating scale(NRS) for pain, ranging from none (0) to extreme (10).The Shoulder Pain and Disability Index (SPADI), a 13-itemscale, was used to assess improvement in shoulder function[11]. A 5-point Likert scale, a subjective assessmentmethod, was used to evaluate patient satisfaction. TheNRS, SPADI, and Likert measurements were performedbefore the treatment and at 3 weeks and 6 months after thetreatment.Two physicians experienced in US-guided suprascapularnerve injections performed the PRF procedures underlocal anesthesia in an operating room. After the patientwas placed in a sitting position, intravenous access wasestablished and routine monitoring was performed. Mild sedation was achieved with 2 mg ofintravenous midazolam bolus at a dose that did not impairthe patient’s consciousness. Chlorhexidine was used forskin antisepsis. The suprascapular notch and the advanceof the needle into the suprascapular nerve were visualizedby US  with a highfrequencylinear probe  . Skin anesthesia was achieved by administering2% prilocaine through a 25-G needle. For an in-planeapproach, a 22-G, 10-cm-long echogenic radiofrequency(RF) cannula with 5-mm active tip  was introduced to the suprascapularnotch . Motor stimulation was performed with2 Hz at a setting of 1 V, and the response was observed atthe deltoid muscle. Subsequently, sensory stimulation wasperformed at 50 Hz at a setting of 0.5 V. Patients definedparesthesia, tingling, and pain in the deltoid and upperarm region. Accurate placement of the needle tip wasdemonstrated via US. After negative aspiration of blood,1 mL of 1% prilocaine was injected. One minute after localanesthetic injection, pulsed RF was performed at 42 °C for360 s. Patients were followed in the postoperative care unitfor 1 h as postprocedural complications could develop.After the data were transferred to a computer, statisticalanalyses were performed using SPSS 21.0 . Descriptive statistics were definedas number, percentage, mean, standard deviation (SD),minimum, and maximum values. The consistency ofcontinuous data with normal distribution was determinedby the Kolmogorov–Smirnov test. The Friedman test wasused to compare continuous data in dependent triplegroups that did not conform to normal distribution. TheBonferroni corrected Wilcoxon test was used to determinewhich binary subgroup was the origin of the differencein the triple groups. In Bonferroni correction, statisticalsignificance level was accepted as P ˂ 0.017. In other tests,P ˂ 0.05 was considered significant.The present study included 31 shoulders of 31 patients whounderwent US-guided PRF procedures of the suprascapularnerve. The mean age of the patients was 66.8 ± 13.3 years,and the mean body mass index (BMI) was 28.1 ± 2.7. Thedemographic and clinical characteristics of the patientsincluded in the study are presented in Table 1.Significant improvements in NRS and SPADI subscoreswere observed in the treated patients in the third week andsixth month after the procedure when compared to thepreprocedural scores (P < 0.001) (Table 2). In addition, nostatistically significant difference was observed betweenNRS and SPADI scores at 3 weeks and at 6 months . Based on the results of the Likert scale,suprascapular nerve PRF treatment resulted in goodpatient satisfaction in 71% patients (22 patients out of 31)at 3 weeks (P < 0.001) and in 68% patients (21 out of 31) at6 months (P < 0.001) . No adverse effectsor complications were observed throughout the follow-upperiod of 6 months.In this study, the efficacy of US-guided suprascapular nervePRF treatment on chronic shoulder pain related to partialrotator cuff tears was investigated. During the 6-monthfollow-up period, most patients demonstrated good pain relief and improved shoulder functionality. To ourknowledge, this is one of the few studies investigating theuse of the US in the application of PRF to the suprascapularnerve.Along with the motor innervation of the infraspinatusand supraspinatus muscles, the suprascapular nerve coversapproximately 70% of the sensory innervation of theshoulder girdle, including the glenohumeral joint, capsule,and acromioclavicular joint [12]. Correspondingly, anisolated blockade of the suprascapular nerve has beendemonstrated to be effective in pain relief after shouldersurgeries [13]. Suprascapular nerve block has beenperformed in joint pathologies, rotator cuff lesions,and other related conditions, providing effective painrelief and functional improvement [13–16]. The useof PRF on peripheral nerves such as the suprascapularnerve has gained popularity in recent years owing to thenondestructive mechanism and low risk of complications.Although the mechanism of pain relief of PRF is not clearlyunderstood, it has been proposed that an electrical fieldis generated at the tip of the needle that penetrates thenerve fibers and causes physiological and ultrastructuralchanges in the nociceptive axons [17]. Another proposedmechanism is that an increase in c-Fos production occursin the posterior horn cells after PRF, possibly affecting theC-fiber transmission by altering the activity of the sodiumchannels . Thus, longer duration of pain relief can beachieved with this technique compared to other treatmentmodalities such as injections of corticosteroids and localanesthetic agents or thermal lesioning [10].In the literature, the first application of PRF to thesuprascapular nerve was applied by Rohof in 2002 with ablind technique [5]. Although the blind technique is stillwidely used, it may cause catastrophic complications suchas pneumothorax, especially in patients with anatomicalvariations [20]. However, Gurbet et al. reported significantpain relief and increase in shoulder function for atleast 3 months after the blind technique suprascapularPRF procedure without any severe complications [21].Instead of the blind technique, fluoroscopy or computedtomography (CT)-guided techniques have been appliedin PRF of the suprascapular nerve [22]. However, in USguidedprocedures, needle advancement is displayedin real time, thereby reducing the likelihood of damageto nerves, vessels, and other adjacent structures [23–25]. Furthermore, when US is compared with CT andfluoroscopy, US does not cause radiation exposure to thepatient or researcher, it is a portable device, and it reducesthe cost of the procedure [26]. Correspondingly, a trendtowards US use has been observed in recent studies. Wu etal. reported improved shoulder function and pain relief forat least 12 weeks after the US-guided suprascapular nervePRF procedure for adhesive capsulitis and concluded thata noticeable reduction in VAS scores could be achieved asearly as 1 week after the procedure [14]. In a recent study,Ergonenc and Beyaz performed US-guided suprascapularPRF for 74 patients and achieved significant improvementsin pain and functionality in the majority of patients duringthe 6-month follow-up period [8]. Therefore, US guidancewas the preferred technique instead of fluoroscopy or CTguidance in this study. As a result, US-guided suprascapularnerve PRF showed significant improvement in shoulderpain and function through the 6-month follow-up period.There were some limitations to our study. The studylacked a control group, and comparison of US-guidedsuprascapular nerve PRF with other treatment modalitieswas not possible. Although good results were obtained atthe end of the 6-month follow-up period, further studiesare needed to evaluate the long-term effects of US use onPRF application to the suprascapular nerve. Finally, dueto the rigid inclusion criteria, the number of patientsincluded in the current study was relatively small, and thismay limit the generalizability of the results of the study.In conclusion, the current study demonstrated thatUS-guided suprascapular nerve PRF is a reliable techniquein partial rotator cuff tears. In the majority of patients,it provides adequate pain relief and an improvement inshoulder functions for at least 6 months. Furthermore,trained physicians can easily repeat this neuromodulationprocedure in the case of recurrence of pain without anydamage to the nerve and neighboring soft tissues underUS guidance.