Excellent and dramatic results with complete remission of symptoms were achieved in 28 cases, and marked improvement was observed in 52 cases, while 22 cases remained unimproved. Many of the patients treated with DMSO had been refractory to cortisone and antibiotic creams. A distinctly longer-lasting effect could be achieved when antibiotics such as tetracycline and erythromy -
cin dissolved in DMSO were applied. 33
Not all studies using topical DMSO for rotator cuff and tendinitis pain showed 
positive results. In a year-long study involving 102 patients presenting with either medial or lateral epicondylitis (tennis elbow) or rotator cuff tendonitis were treated with topical applications of DMSO. Beneficial effects were assessed with respect to improvement in pain, tenderness or swelling, and increase in the range of motion. Forty patients treated with topical 70% DMSO aqueous solution did not report any more benefit from the drug than patients who received a 5% DMSO aqueous placebo solution. 34
A review of DMSO in otological conditions by Freeman35 in 1976 claimed that a 
thorough review by him of the literature revealed no evidence that topical application of the drug was useful and concluded that although DMSO was not ototoxic, double-blind studies on patients with otological infections demonstrated that 90% DMSO 54 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
applied within the external auditory canal had no anti-inflammatory, antibacterial, 
or analgesic properties, and there was no evidence that it potentiated the action of other medicines when mixed preparations were used. To support this conclusion, Freeman
35 cited 11 references in his review, most of which in fact supported the 
opposite conclusion from that derived by Freeman,35 who referred to “many double-
blind studies” that demonstrated the lack of activity by DMSO but never once cited any of these reports or references. Such shoddy and scientifically lazy conclusions failing to cite any report in sup -
port of its tenet would haunt DMSO for years as the shroud of its mystique and sometimes enthusiastic hyperbole by its supporters grew exponentially to the degree of putting into question the credibility of many evidence-based and well-performed experiments, both basic and clinical, that showed either positive or negative findings for the actions of this molecule on a variety of models and systems. Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic 
dystrophy and causalgia, is a chronic systemic disease characterized by intense neu -
ropathic pain out of proportion to the severity of the injury. 36 CRPS can result from 
even a mild tissue trauma to an extremity, and when it does, it is typically character -
ized by swelling and severe pain of the extremity and by dramatic color and tempera -
ture skin changes.37 There is no specific test that can diagnose CRPS, and diagnosis 
is often made by the exclusion of similar pain conditions. CRPS is divided into two types: CRPS-1, which lacks demonstrable nerve lesions, 
and CRPS-2, formerly known as causalgia, where the pain is generally neuropathic and more severe than type 1 and where evidence of nerve damage is present. 38
The specific cause of CRPS is not known for certain, but dysfunction or damage 
to the peripheral or central nervous system (CNS) may follow a nerve injury after trauma or surgery. 39
Another theory is that CRPS is caused by an immune response that leads to the 
changes seen in the skin (redness, warmth, swelling, and pain) involving proin-flammatory mediators such as TNF-alpha, interleukins 1 β, 2, 6, 8, and C-reactive 
 protein,40–42 as well as increased systemic levels of proinflammatory neuropep -
tides, including substance P and bradykinin.43 Other findings indicate that when 
there are no clinical signs of peripheral nerve damage, posttraumatic focal CRPS-1 is nonetheless associated with significant loss of C-fibers and A- δ fibers in the 
affected area. 44
About 50,000 new cases of CRPS are estimated to occur annually in the United 
States alone (Bruehl), generally following surgery, simple fractures, crush injuries, and sprains. 38 When a limb is affected, loss of strength and decreased active range of 
motion can disable the individual, resulting in continuous intense pain and psycho -
logical stress. In fact, the pain can be so intense in CRPS that it has the unfortunate honor of being described as the most painful syndrome or disease, scoring highest on the McGill pain scale (42 out of a possible 50), and considerably above such events as amputation of a digit and childbirth (see Figure 3.1). After many randomized-controlled trials published, there is no clinical consensus 
on how to treat or manage CRPS. 45
Pathophysiologically, oxidative damage by free radicals have been implicated in 
the development of CRPS.46 In addition, pain sensation that increases with time, 55 DMSO Clinical Pharmacology
also called wind-up , and CNS sensitization are important neurologic processes that 
have been reported to be involved in the unfolding of CRPS.47 In this regard, it is 
interesting to note that elevated CNS glutamate levels promote wind-up and CNS 
sensitization.47
In addition, there is experimental evidence that demonstrates that N-methyl- d-
aspartate (NMDA) receptors are localized in peripheral nerves and appear to be activated following CRPS. 48 Moreover, there is compelling evidence that the NMDA 
receptor has significant association in the CNS sensitization process involving CRPS. 49 This finding has led to the use of NMDA receptor blockers and free radical 
scavengers as a primary target for neuropathic pain48 that can lead to central sensiti -
zation and wind-up  phenomena such as that seen in CRPS.50
Good to excellent results in pain control of patients with CRPS type 1 have 
been shown after the topical application of 50% DMSO over the affected area.51 
The results indicated significantly favorable pain management, particularly when the CRPS was associated with inflammatory symptoms. 51 The mechanism by which 
DMSO is able to provide pain relief in one of the most difficult to treat pain condi -
tions remains unclear. A clue may lie in the fact that DMSO acts as a powerful free radical scavenger, 
and it is well known that free radicals following injury can be toxic to tissue and introduce acute or chronic pain sensation. DMSO is also an NMDA and glutamate receptor antagonist, and both substances can activate hyperalgesia and neuropathic pain. CRPS
Amputation of dig it50
40
30
20
10
0Chronic back pain
Phantom limb painChildbir th pr imipara
Childbir th multipara
Nonterminal cancer
Fracture
FIGURE 3.1  The McGill Pain Index is a subjective measure used clinically to compare 
pain perception from 0 to 50 in patients and provide a guideline for analgesic efficacy. CRPS 
is nearly at the 50-point mark, the highest pain sensation felt by humans. The analgesic least likely to do harm and provide good efficacy in the treatment of CRPS was reported to be DMSO. (From Quisel, A. et al., J. Fam. Pract ., 54(7), 599, 2005. )56 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
One of the cardinal features of inflammatory states is that normally innocent 
stimuli can produce severe pain. This may be one of the mechanisms targeted by 
DMSO as an anti-inflammatory agent. Finally, DMSO has the ability to block C-fiber and small fiber pain fibers after its topical application. These actions may explain to some degree the number of studies that have tested DMSO in hundreds of patients where controlling pain and the consequences of CRPS were achieved. 23,26,51–53
To compare the effects of two free radical scavengers, topical 50% DMSO and 
N-acetylcysteine (NAC) were used for the treatment of CRPS-1, in a randomized, 
double-dummy controlled, double-blind trial.3 Treatments were conducted in 146 
patients over a period of 24 months. Patients were randomized into two treatment groups: one was instructed to apply DMSO 50% five times daily to the affected extremity, and the second was treated with NAC 600 mg effervescent tablets three times daily, and both treatments were compared to each other and to a placebo. Significant differences were found for subscores of lower extremity function, in favor of DMSO treatment. 3 Subgroup analysis showed more favorable results for DMSO 
for warm CRPS-1 than for NAC.3
A study by Gaspar et al.54 evaluated the topical treatment of 50% DMSO cream 
in type 1 CRPS over a period of 15 days, 1 month, 3 months, 6 months, and 1 year in 29 patients. The evaluation was performed using primarily a visual analogue scale (VAS) as the main efficacy variable that measures the patient’s pain intensity subjectively. Secondary measures of efficacy by DMSO included the quality of life after treatment and the physical mobility of the affected limbs, involving range of motion, strength, and overall limb function. The results showed that topical appli -
cation of 50% DMSO significantly diminished pain intensity approaching absence of pain, according to the VAS score at each period of observation. Secondary measures of efficacy were also recorded as higher scores on the quality of life questionnaire with a general improvement on limb rigidity, mobility, and func -
tion. 54 Thus, this study by Gaspar and his team54 complies with the QFW values  
for the quality of easing pain (Q), restoring or significantly improving anatomic–physiological function (F), and general well-being (W) expressed by the patients following treatment. One of the first studies to recognize the usefulness of DMSO in the treatment 
of CRPS was reported by Goris
55 in 1985. Goris55 showed that DMSO as an anti-  
inflammatory and free radical scavenger agent could reduce the inflammation 
 associated with CRPS and demonstrated, in an open study, a reduction of the CRPS 
symptoms using 50% DMSO cream. These results led to a prospective,  r andomized, 
and double-blind study on 32 patients following an accidental trauma and the devel -
opment of acute CRPS.56 Patients showed increased temperature,  r edness, and pain 
in the affected extremity, coupled to a limited range of motion of the limb. A VAS was used to measure the redness, swelling, and limited active range of motion of  the affected extremity. DMSO 50% cream applied five times daily was com -
pared to a placebo cream for 2 months. After 2 months, DMSO showed significant 
(p < 0.01) improvement of the VAS measures as compared to the placebo cream, 
and the authors recommended further use of DMSO for CRPS. 56 Side effects from 
the DMSO  a pplications were mild scaling of the skin in the affected areas, which 
resolved in time.5657 DMSO Clinical Pharmacology
More recently, topical application of 50% DMSO three to five times daily was 
given as an anti-inflammatory therapy to 74 patients with CRPS and a mean dis -
ease duration of 17 weeks.57 The DMSO treatment was supplemented with physical 
therapy and acetaminophen as an oral analgesic. Of the 74 patients with early CRPS, 
55 (74%) patients significantly showed improvement in their pain score. Although no attempt was made to examine whether analgesia was obtained with DMSO or acetaminophen, the authors concluded that this package treatment should become standard therapy for patients presenting with early CRPS. 57
A review of the most promising treatments for CRPS-1 at the present time con-
cluded that early treatment of this syndrome is more likely to respond to treatment.58 
Of all the therapies for CRPS considered, including a wide range of analgesics, gan -
glionic blockers, steroids, adrenoceptor antagonists, acupuncture, calcitonin, and the glutamate blocker ketamine, the authors concluded that the therapy least likely to do 
harm and supported by evidence of efficacy  was topical 50% DMSO cream
58 (see 
Figure 3.1). In dealing with the subject of pain in humans, it must be remembered that pain is 
one of the most subjective of conditions and consequently one of the most difficult to test objectively by any means. Many extrinsic and intrinsic factors such as varying pain thresholds, gender, age, level of stress, culture, health status, mental condition -
ing, and other factors make pain a unique ailment in assessing and successfully treating it. Pharmaceutical-grade DMSO has been used extensively as a penetration enhancer 
over the past 30 years demonstrating a favorable safety and efficacy profile. DMSO enhances the transdermal delivery of both hydrophilic and lipophilic medications that can provide localized drug delivery. NSAIDs are widely used in the treatment of pain associated with a variety of 
indications, including arthritic conditions, but their usefulness is often limited by dose-dependent adverse events, such as gastrointestinal disturbances, cardiovascular events, and renal toxicity. The risk of such effects could be reduced by the use of topical formulations, which offer the potential to deliver analgesic concentrations locally, at the site of inflammation, while minimizing systemic concentrations. In view that DMSO can potentiate the pharmacological activity of other agents 
and carry many of these compounds to a biological system, a number of DMSO mix -
tures have been described for a variety of medical conditions. In managing osteoar -
thritis, a condition with no cure characterized by pain, stiffness in at least one joint, and impairment or loss of function of the affected joint(s), diclofenac sodium topical solution 1.5% in 45% DMSO (TDiclo) was approved by the FDA in 2009 for the treatment of osteoarthritis. This NSAID–DMSO preparation now offers an alterna -
tive to single-use (NSAID) agents by reducing the NSAIDs risk of adverse events through DMSO’s ability to enhance the penetration of diclofenac and thereby lower the dose of diclofenac. 59–61
A recent multicenter, randomized, blinded, Phase III clinical study lasting 4–12 
weeks of TDiclo for knee or hand osteoarthritis in 280 patients over the age of 75 reported that TDiclo is an appropriate treatment choice for osteoarthritis, with rela -
tively few patients experiencing gastrointestinal or rarely cardiovascular and renal/urinary adverse events. 62 Results from this study suggest that TDiclo may offer an 58 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
alternative to oral NSAID therapy for osteoarthritis of the knee or hand, particularly 
for patients at increased risk for serious systemic adverse events from oral NSAIDs.62
Prostate cancer is the most common cancer in men. Although it generally affects 
older men, it causes significant mortality when it metastasizes. The main therapy for metastatic prostate cancer involves androgen manipulation, chemotherapy, and radiotherapy. 63
Prostate cancer pain is difficult to treat because the pathophysiology of pain in 
cancer patients is complex and remains poorly understood, making intractable pain from cancer a challenge for both patients and clinicians. 64
Infusion of DMSO–sodium bicarbonate (DMSO–SB) was used to treat 18 patients 
with metastatic prostate cancer.65 After a 90-day follow-up, patients treated with 
DSMO–SB showed significant improvement in clinical symptoms, including pain, blood and biochemistry tests, and quality of life. 65 There were no major side effects 
from the treatment. This study strongly suggested that therapy with DMSO–SB infu -
sions could provide a rational alternative to conventional treatment for patients with metastatic prostate cancer. 65
Another approach for the palliative treatment of advanced prostate cancer involved 
a subcutaneous implanted device that uses DMSO as a solubilizing  e xcipient. The  device was approved by the FDA in 2000. The implanted device contains a solution of 104 mg of DMSO and 72 mg of leuprolide acetate
66 (Viadur), a synthetic 
form gonadotropin-releasing hormone that can decrease blood levels of the male hormone testosterone. Androgen deprivation using leuprolide acetate and DMSO as an excipient has been shown to have a salutary effect in men with advanced prostate cancer. 67 In two open-label multicenter studies, long-term efficacy and safety using 
Viadur implanted device for 1 year was reported in a total of 122 patients.68
Among the many antiviral agents used against herpes simplex virus (HSV), idox -
uridine and adenine arabinoside have shown minimal therapeutic benefit. However, 
when combined with DMSO, this treatment has been successful in acyclovir-  r esistant 
strains of HSV. In a double-blind, randomized, patient-initiated treatment study at five medical centers, 301 immunocompetent patients experiencing a recurrence of herpes labialis were treated with topical 15% idoxuridine (IDU) in 80% DMSO. 69 
Using this drug combination, the mean duration of pain was significantly reduced by 1.3 days and the mean healing time to loss of crust by 1.7 days. 69 When only patients 
with classic herpes lesions (vesicle, ulcer, or crust formation) were considered, a greater drug effect using the idoxuridine–DMSO combination was seen for lowering the duration of pain by 2.6 days and increasing the mean healing time to normal skin by 2.3 days, a significant difference when compared to controls. 69
Idoxuridine–DMSO (IDU) has also been used for herpes zoster and for the pre -
vention of post herpetic neuralgia and compared to the antiviral agent acyclovir. After 4 days of topical treatment, IDU showed better control of vesicle formation, itching, and pain than oral acyclovir or placebo. 70
These studies support the concept of DMSO as a penetrant and enhancer of other 
pharmaceuticals and suggest that additional combinations of DMSO and proven active medications for many illnesses should be further studied with the goal of lowering the dose of the active agent and consequently their systemic toxicity by localizing the treatment to a body part. This pharmacotherapeutic approach has not 59 DMSO Clinical Pharmacology
been exploited to a greater potential, especially with newer active agents for disease 
control that are replacing older, less efficacious, and more toxic medications. The effects of DMSO as a neuroprotective agent in the brain and spinal cord are dis -
cussed in more detail in Chapters 8 and 9. INTERSTITIAL CYSTITIS
Interstitial cystitis (IC) is a painful chronic bladder condition that causes debilitating bladder pain that can be associated with urinary urgency, frequency, and nocturia. It is characterized by inflammation, erosion, and thinning of the bladder epithelial cells, and its hallmark symptom is pelvic and perineal pain. IC affects about three to eight million women and one to four million men in the United States, reducing the quality of life and social function of those affected. IC often overlaps overactive bladder (OAB), which can make diagnosis of either one or both difficult. 71 It is gen -
erally accepted that the hallmark for IC is pain and abdominal tenderness, whereas for OAB, it is urgency, frequency, and nocturia. However, both conditions can share these complaints. The cause of IC is not clear, and it is still a disease diagnosed by exclusion since 
many other conditions resemble the symptoms of IC. There is no definitive test to identify IC, but other conditions mimicking IC can be ruled out by urinalysis, urine culture, cystoscopy, biopsy of the bladder wall, and, in men, laboratory examination of prostatic secretions. IC is an understudied disorder lacking diagnostic and strategic treatment modali -
ties, most likely from the limited research funding available to investigators. 72 Oral 
or intravesical therapies are the mainstay of treatment, while surgical procedures are reserved for refractory cases. This condition usually warrants a multidisciplinary approach for optimum outcome. 73
In 1978, Shirley and his colleagues74 introduced DMSO as a treatment for IC and 
reported dramatic results. They treated 213 patients with a variety of inflammatory conditions involving the lower genitourinary tract. These conditions included intrac -
table IC, radiation cystitis, chronic prostatitis, and chronic female trigonitis. 74
In this series by Shirley and his colleagues, the use of intravesical instillation of 
DMSO resulted in an excellent or good response in 54% of the female patients with no serious side effects noted. The treatments, however, are not curative and fre -
quently require long-term maintenance with periodic installation of DMSO. This initial report was followed by more studies from the same group and by 
others,
75,76 confirming the effectiveness of intravesical DMSO in controlling the 
symptoms of IC. Some reports showed 93% improvement in IC symptoms compared to 35% in the placebo group. 76 These early reports were followed by independent 
research studies from many countries, and by the end of 1978, DMSO was the first drug treatment approved by the FDA for the symptomatic relief of IC. Presently, DMSO remains the sole intravesical instillation agent for IC. The brand name for 
DMSO use in IC is RIMSO-50. In clinical practice, the urinary bladder is filled with 50% DMSO for 15  min 
as a treatment for IC (Figure 3.2). This approach has the advantage that it reduces 
side effects from systemic application by achieving a high concentration of the drug 60 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
locally in the bladder. The initial disadvantage of bladder instillation was that it 
required a health-care provider to perform the procedure on patients during a clinic visit. By 1987, patients did not need to go to a clinic to have DMSO instilled in their 
bladders, but they could be taught to self-administer DMSO at home using special kits. 77 No complications have been noted when the patient is taught how to self-
administer DMSO. The effectiveness of intravesical instillation of DMSO can be summarized as 
follows:
 1 . I t reduces bladder inflammation and pain.78,79
 2 . I t helps relax the bladder and pelvic detrusor muscles, thus reducing muscle 
spasm80; detrusor fibrosis is found in approximately 53% of IC patients and 
may be a major factor in treatment failure.81
 3 . I t relieves pain by reducing small nerve fiber conduction of pain fibers, by 
diminishing inflammation, and by lowering substance P (a neuropeptide associated with pain) from bladder nerves. 23,82,83
 4 . I t helps reduce scar tissue by preventing collagen formation that promotes 
scarring.84
 5 . I t reduces erosion and thinning of the bladder wall by limiting inflamma -
tion78,79 (Figure 3.2). The contractility of the bladder is attenuated after the intravesical treatment with DMSO, and it is reasonable to assume that the relaxant effect of DMSO is related to its therapeu -
tic effect in relieving the inflammatory-related symptoms associated with IC. 85,86
Erosion and thinning of
bladder epithelial cells
improve d with 50% DMSO
instillation 
IC reduction of inflammation
with DM SO instilla tionNormal bladderKidne ys
Ureters
Bladder
Urethra
FIGURE 3.2  (See color insert.) DMSO instillation for interstitial cystitis.61 DMSO Clinical Pharmacology
When IC is refractory to DMSO instillation, DMSO bladder cocktails  have been 
tried with some success. These cocktails entail mixing DMSO with heparin, ste -
roids, hyaluronic acid, analgesics, and other substances.87,88
GASTROINTESTINAL DISORDERS
Despite the presence of inflammatory changes in many gastrointestinal disorders, 
not much research has been reported using DMSO as an anti-inflammatory agent in these conditions. Most of the studies using DMSO in inflammatory bowel disease have been done outside the United States. One use of DMSO in gastrointestinal disorders has aimed at Crohn’s disease with 
secondary amyloidosis (AL), which develops in approximately 1% of patients with Crohn’s disease. Oral administration of DMSO in 15 patients was found to be an effective treatment for amyloid A AL complicating gastrointestinal involvement and the early stage of renal dysfunction. 89 DMSO was given in three equal doses after 
meals at a dose of 3–20 g/day in a 33% solution with water or juice for 8 weeks. This treatment was observed to improve the renal function in 5 out of 10 renal AL patients when DMSO was initiated early in the disease process but had no effect on those patients with severe and/or advanced renal dysfunction. 89 In six patients, specific 
improvements were seen in gastrointestinal AL, gastrointestinal symptoms, includ -
ing diarrhea, and protein-losing gastroenteropathy.89
Salim90 used DMSO as a free radical scavenger on patients with recurrent ulcer -
ative colitis and reported that 51% of patients receiving sulfasalazine and predniso -
lone alone showed good symptomatic control after 2 weeks of this regimen, and when DMSO was added to this treatment, 84% of patients showed similar symp -
tomatic benefit. 90 This author concluded that oxygen-derived free radicals may be 
involved in the pathologic process of ulcerative colitis and that blocking these free radicals promoted the protection of the colon against recurrence of attacks. 90
AUTOIMMUNE DISORDERS
In 1980, Pestronk and Drachman91 reported that humoral immune mechanisms play 
an important part in the development of myasthenia gravis (MG). MG is a chronic autoimmune disorder in which circulating antibodies cause progressive weakness of the skeletal muscles by blocking acetylcholine receptors at the postsynaptic neuro -
muscular junction. The disease most commonly begins by weakening the muscles that control eye movements and eyelids, an effect that produces blurring, double vision, and eyelid drooping. In time, other muscle groups are affected, making chew -
ing, swallowing, and breathing a life-threatening situation. In the 1980 report, Pestronk and Drachman
91 noted that in the course of testing 
immunosuppressive drugs that could treat experimental autoimmune MG, they dis -
covered that DMSO used as a vehicle to dissolve some of these agents itself produced 
a rapid and sustained fall of anti-AChR antibody titer. This observation led to their 
confirmation of this finding when DMSO was used on an experimental rat model of MG. It was seen that DMSO suppressed anti-AChR antibody levels by an average of 53%–76%, an effect that was similar whether DMSO was given by oral, rectal, or 62 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
intraperitoneal routes.92 DMSO treatment also suppressed the anti-AChR antibody 
response to a weak primary antigenic stimulus in the MG rat model.92
More recent studies on experimental autoimmune cystitis reveals that DMSO 
can impair effector T cells in a dose-dependent manner in vitro .93 Effector T cells 
secrete inflammatory cytokines such as interleuli-6 in the bladder, which is con -
sidered to be responsible for the development and propagation of painful bladder 
symptoms in IC.94
There have been no human trials using DMSO for any autoimmune disorder, 
including MG.
RESPIRATION
DMSO has been shown to be an effective respiratory stimulant in experimen -
tal hypoxic states and following brain trauma in nonhuman primates95,96 (see also 
Chapter 2). These findings led Klein and his colleagues97 to use DMSO in patients 
with acute respiratory distress syndrome (ARDS). ARDS is a severe lung syndrome characterized by inflammation and edema of the lung parenchyma causing hypox -
emia that can lead to multiple organ failure and death. 98,99 Most often, ARDS can 
result from sepsis or trauma, but shock and substances that will damage the alveolar epithelium can bring about a reaction. 98
Klein et al.97 reported that based on the properties that were known at the time 
for DMSO, such as a mucolytic respiratory stimulant, and its ability to lower tis -
sue oxygen requirements, 10% DMSO was given intravenously to three near-death patients who had not responded to conventional treatments. All three patients responded to the DMSO administration within an hour, showing a significant rise in paO
2 from the 60s to high 80s and 90s and oxygen saturation increasing sub -
stantially to 95% within 8 h. The authors concluded that DMSO as a treatment for ARDS merited further investigation in view of the difficulty in treating this syndrome. AMYLOIDOSIS AND SCLERODERMA
Primary systemic AL is characterized by the deposition of insoluble amyloid pro -
teins in various organs contributing to the dysfunction of these organs. The median survival of patients with AL is 12 months, and if heart failure is present, mean sur -
vival is 6 months after the onset of symptoms. 99 Thus, the ability to dissolve the amy -
loid deposits or block their production would be expected to improve the affected organ function and extend survival. The beneficial effects of DMSO on amyloid deposition were first reported by 
Isobe and Osserman
100 in 1976, and since then, a number of reports have confirmed 
the usefulness of DMSO therapy on organ damage caused by AL.89,101 There has 
been some controversy that DMSO may inhibit amyloid production or act principally 
as an anti-inflammatory agent or free radical scavenger in organ damage associated 
with AL rather than a dissolver of amyloid fibrils.102
By contrast, single-case studies, though anecdotal, are occasionally of interest 
because they can provide clues as to the effectiveness of DMSO in disorders such as 63 DMSO Clinical Pharmacology
AL, where a major clinical trial is not feasible. Such a case study was described of a 
patient with multiple myeloma who developed pulmonary infiltrates caused by AL and was given transdermal DMSO for 8 weeks, which resulted in a dramatic regres -
sion of the pulmonary infiltrates shown by x-ray analysis together with the stabiliza -
tion of arterial blood gases. 103
This report received confirmation in another case study of pulmonary AL treated 
with 10 mL DMSO per day for 2 years 104 (sutani). In a disorder that is known to progress rather aggressively within months of symptom onset, DMSO treatment resulted in significant reduction of pulmonary nodules and slowdown of disease progression. 104
Similarly, it was reported that seven patients with secondary AL showed an 
unequivocal improvement of renal function following 3–6 months of 7–15 g/day of continuous oral DMSO treatment, which resulted in a 30%–100% rise of creatinine clearance and a decline in amyloid subunits in the urine that suggested breakdown or mobilization of the amyloid fibrils out of the tissue into urine. 105 This improvement in 
renal function was maintained as long as DMSO treatment was continued.105
Scleroderma is a connective tissue disease that involves changes in the skin, blood 
vessels, muscles, and internal organs, and it is thought to be caused by the accumula -
tion of collagen.106 It should be noted that DMSO application has been reported to 
reduce collagenous fibers in animals and in scleroderma patients.107,108
Scherbel109 reported that cutaneous ulcers in scleroderma (systemic sclerosis) were 
seen to resolve after 2 weeks following topical applications of 35% DMSO applied three times daily. Patients receiving 35% DMSO had the topical dose increased to 46% after 2 days, and DMSO applications were reduced as ulcer healing appeared. As ulcers healed during a 6-month observation period, joint motion, grip strength, and skin softening were recorded to improve in 19 of 22 patients who participated in the study. 109
However, a prospective, randomized, double-blind trial that compared topical 
therapy using 0.85% normal saline, and 70% DMSO for the treatment of digital ulcers in 84 patients with systemic sclerosis failed to show any difference between saline control and DMSO application with respect to total number of open ulcers, total surface area of open ulcers, average surface area per open ulcer, and the number of infected or inflamed ulcers. 110
THROMBOEMBOLIC EVENTS
Myocardial infarction (MI) and ischemic stroke are leading causes of death and dis -
ability worldwide. Both conditions share a common pathologic process that results from unstable and vulnerable atherosclerotic plaques that form on the inside walls of coronary, peripheral, and cerebral arteries. 111 These plaques can rupture from 
high shear stress and trigger a thromboembolic event leading to an MI or ischemic stroke. 112
Atherosclerotic plaques are composed mainly of extracellular lipid-rich material 
inside and outside of cells together with connective tissue components such as cho -
lesterol and accumulated macrophages from the bloodstream. Coronary artery dis-ease (CAD) generally precedes MI sometimes by decades, but the harm results when 64 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
the coronary arteries become partially or totally blocked by atherosclerotic plaque 
formation. Rupture of an atherosclerotic plaque can activate platelets to form a clot that can dislodge and travel to a coronary or a cerebral artery where partial coronary occlusion can induce anginal pain, and a total occlusion can result in an MI or an ischemic stroke. Thus, apart from their role in primary hemostasis, platelet activation is also criti -
cal in atherothrombosis where platelet adhesion and aggregation in the local micro -
environment stimulate the release of their own inflammatory mediators to promote life-threatening cardiovascular and cerebrovascular thrombotic events. 113
In addition to their role in acute thrombus formation, platelets are able to foster 
a complex inflammatory response that influences atherosclerotic lesion progression and induces plaque rupture. 114 Platelets involved in vascular inflammation appear 
to interact with endothelial cells, macrophages, and smooth muscle cells to create a pathologic fibroproliferative state. 115
The route of entry of platelets into the atherosclerotic plaque and their exact loca -
tion inside the plaque are, however, not completely understood. The key role played by platelets in atherothrombosis has led to the search of effective and safe antiplatelet agents that can block platelet aggregation. Platelet-mediated thrombosis is dependent on three steps: (1) activation, (2) aggre -
gation, and (3) adhesion, and each of these steps is a potential therapeutic target for the development of antiplatelet agents. Only platelet adhesion antagonists have not been approved for clinical use. Antiplatelet treatment is a clinically crucial mainstay in acute and long-term 
secondary thromboembolic prevention. Antiplatelet drugs that work on different receptor sites of the platelet have been found to be extremely effective in preventing cardiovascular and cerebrovascular events and their recurrence, especially in high-risk patients and patients undergoing a percutaneous coronary intervention. 115,116
These antiplatelet drugs include platelet-activating inhibitors such as aspirin that 
can irreversibly block cyclooxygenase-1 (COX-1) and the formation of prostaglandin PGH
2, the precursor of the powerful platelet aggregant and vasoconstrictor, throm -
boxane A2.117 It has been reported that PGH2 and thromboxane A2 receptors are 
found to be increased in patients with acute MI.118
The benefit of aspirin used alone or in combination with other antiplatelet drugs 
has been extensively studied as a primary and secondary prevention of thrombotic events in patients at high risk of cardiovascular and cerebrovascular embolism. 119,120
The main problem with using aspirin to prevent the recurrence rate of ischemic 
events, aside from its bleeding potential, is that it targets only the COX-1 pathway and therefore cannot take aim at other pivotal signaling pathways, which can also lead to coronary and cerebrovascular thrombosis. A second group of platelet activation inhibitors currently approved for clinical 
use are the thienopyridines such as ticlopidine, clopidogrel, and prasugrel, which target the blockade of the platelet ADP receptor P2Y
12.121 It is well known that P2Y12 
receptor-mediated signaling processes play a central role in platelet activation and aggregation. 122 ADP is a potent platelet-aggregating agent that was originally shown 
to induce myocardial ischemia and arrhythmias when injected experimentally into the coronary arteries of pigs. 12365 DMSO Clinical Pharmacology
Clopidogrel is currently the PY212 receptor antagonist of choice, although its 
broad interindividual variability in patients resistant to this antiplatelet drug and its 
delayed onset of action that can take 4–5 days before reaching its maximum anti -
platelet effect has resulted in a considerable number of adverse cardiovascular and ischemic events. 124 These adverse events in patients treated with clopidogrel have 
reduced its clinical expectations as a safe antiplatelet agent.124,125
Despite this concern, the antagonism of the P2Y12 receptor with clopidogrel has 
been shown to be clinically effective in the prevention of MI, ischemic stroke, and vascular death. 126 Nevertheless, there is hope that a more clinically effective and 
safer P2Y12 antagonist will be found to prevent the incidence of ischemic and cardio -
vascular events.126
To increase its efficacy, clopidogrel has been combined with aspirin and found 
more effective than aspirin alone in acute coronary syndrome and stroke.127–129 It is 
also reasonable to speculate that dual antiplatelet therapy such as the combination of clopidogrel–aspirin is more effective than either monotherapy because it targets two 
antiplatelet pathways, for example, ADP-induced platelet aggregation (clopidogrel) and thromboxane A
2 platelet aggregation (aspirin). However, there is a rising concern that dual therapy using clopidogrel–aspirin 
increases the risk of bleeding due to the powerful anti thrombotic effect of using two anticoagulants than using aspirin monotherapy. 130 More importantly, the possible 
synergy of this dual therapy has been reported to be no better than aspirin alone with respect to lowering the rate of MI, stroke, or death from cardiovascular causes. 122,130
Other antiplatelet agents used clinically include thrombin receptor antagonists 
such as the phosphodiesterase (PDE) inhibitors dipyridamole and cilostazol.131
Since thrombin is the most potent platelet activator known, there is hope that 
thrombin antagonists represent a promising novel strategy to reduce ischemic events without increasing the risk of bleeding or cardiovascular events, as other antiplatelet agents are prone to do. 132,133
In this sense, a monotherapy that could antagonize platelet aggregation induced 
by more than one signaling pathway might offer improved efficacy and better safety than dual antiplatelet therapy because it would avoid the powerful anti thrombotic effect that is typically seen from two strong anti thrombotic agents that can lead to life-threatening bleeding complications as shown by clopidogrel–aspirin. 134
DMSO has been shown to possess several unique pharmacological activities that 
could identify it as an antiplatelet monotherapeutic drug for use against CAD and stroke. DMSO combines four crucial properties that have been consistently sought in 
a drug to help prevent primary and secondary thromboembolic events: (1) platelet 
deaggregation , (2) tissue factor antagonism , (3) free radical scavenging , and (4) 
anti-inflammation. These properties resemble those observed with aspirin, which is also an effective 
anti-inflammatory and antiplatelet agent that blocks the production of prostaglandins 
by blocking the COX-1 pathway and consequently the synthesis of thromboxane A
2. As will be seen later, DMSO, unlike aspirin, also blocks tissue factor, a precursor of 
the powerful platelet aggregator thrombin, and additionally shows consistent activity as a free radical scavenger.66 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
These activities by DMSO target two different signaling pathways known to 
induce platelet aggregation, namely, the prostaglandin cascade and thrombin activa -
tion. It remains to be seen in future clinical trials of DMSO whether targeting two 
different signaling pathways involved in platelet aggregation enhances its pharma -
cotherapeutic potential to prevent or reverse coronary thrombosis and stroke events. This section will examine how these activities reported by DMSO could serve to 
provide patients at risk or at recurrence of CAD and stroke with significant short- or long-term prevention. PLATELET DEAGGREGATION AND FREE RADICAL SCAVENGING
An early report by White135 in 1971 reported the antiaggregatory property by DMSO 
for platelets incubated in platelet-rich plasma. This report was followed by an extended study from the same author and his colleagues,
136 that showed how DMSO 
might exert its antiaggregation activity on platelets. An antibiotic ionophore A23187 was used to produce rapid, irreversible concentration-dependent platelet aggregation in vitro. 136
It was observed that the elevation of the cyclic 3 ′,5′-adenosine monophosphate 
(cAMP) level in platelets inhibited the response to all aggregating substances used in that study, including the A23187 ionophore. It was found that 10  mM DMSO added to the platelet-rich plasma was able to deaggregate these platelets ostensibly by increasing the level of cAMP in platelets following A23187-induced aggregation. 136
Although it was not entirely clear in 1974 how DMSO was able to influence plate -
let cAMP in vivo , one suggestion was that DMSO altered platelet membrane fluidity 
to indirectly increase intracellular cAMP.137
Görög and Kovács138 reported soon after the studies by White that topically 
applied DMSO was effective against platelet thrombi induced by ADP, a power -
ful platelet aggregator, when placed in the microcirculation of the hamster’s cheek pouch. 138 These investigators also observed that 10% DMSO topically applied to a 
platelet-occluded venule preparation isolated from rat mesentery was able to inhibit thrombus formation in those venules when flow was experimentally restored. 138
One of the more curious reports showing the antiaggregatory activity of DMSO 
was shown by Pace et al.139 in 1983. This team, working for a major pharmaceuti -
cal, was investigating potential agents for the treatment of ischemic cardiac disease on a canine model when they made the mistake of using DMSO as a diluent for the experimental platelet deaggregators. Like good scientists, they observed the strange finding that most of the experimental agents tested had almost identical excellent antiaggregatory properties when dissolved in DMSO, at which point, when they tested DMSO by itself, they realized to their dismay that when 1 g/mL of DMSO was injected into a partially stenosed left circumflex branch of the left main coro -
nary artery, the low coronary blood flow stemming from the stenosis was reversed. 139
These findings were later confirmed by Levett and his team,140 who infused 50% 
DMSO intravenously using a similar canine model of myocardial ischemia obtained by the ligation of the left descending coronary artery. They reported that cardiac output increased significantly, and both systemic and cerebrovascular resistance decreased in the DMSO-treated animals as compared to controls. 14067 DMSO Clinical Pharmacology
On the question of how DMSO may deaggregate platelets, it has been shown 
that DMSO can increase cAMP accumulation in platelets by inhibiting its break -
down enzyme, the cyclic nucleotide PDE, a reaction that was observed in human 
peripheral blood lymphocytes in vitro .137 This action on PDEs by DMSO could be 
similar to that of cilostazol, a promising therapeutic drug for patients at risk of isch-emic stroke and major adverse cardiac events. 141 Cilostazol exerts its antiaggregation 
activity by selectively inhibiting PDE type 3.142
It should be noted that, at the present time, platelets are known to possess three 
PDEs, PDE2, PDE3, and PDE5, of the 60 different platelet isoforms described in mammalian species. 143,144 It is not yet known which of these PDEs DMSO targets for 
the inhibition of platelet aggregation. PDEs are fundamental for platelet function, and their inhibition can dampen 
platelet aggregation by increasing cAMP and cyclic guanosine 3 ′–5′-monophosphate 
(cGMP), an action that limits the levels of intracellular nucleotides.145
Increasing cAMP by DMSO also implies that DMSO may serve an important 
function in manipulating signal transduction mediated by second messenger mol -
ecules such as cAMP. Inhibition of platelet signal transduction may suppress platelet activation regardless of the initial stimulus. 143 As mentioned before, DMSO could 
achieve this not only by directly inhibiting platelet-activating second messengers like cAMP and cGMP but also by amplifying the action of the endothelium-derived PGI
2, which can indirectly increase intracellular platelet cAMP.143
The ability to inhibit PDE enzymes has great clinical significance because it can 
prolong or enhance the effects of physiological processes mediated by cAMP, espe -
cially where cAMP plays a role in coronary heart disease. For example, it is gen -
erally recognized that prostacyclin (PGI2) is the most potent inhibitor of platelet 
aggregation and that this action involves the production of cAMP.146,147
PGI2-induced inhibition of platelet aggregation is mediated by the increase in cel -
lular cAMP level through the activation of membrane adenylate cyclase, a process that starts as PGI
2 binds to its receptors on the platelet surface.148
It is known from the early studies of LaHann and Horita149 that DMSO is able to 
stimulate the antiplatelet prostanoid PGE1 and that at low doses in some in vitro  sys-
tems, it also blocks prostaglandin biosynthesis and platelet aggregation induced by arachidonic acid. 22 These findings imply that low or high doses of DMSO can have 
a stimulating effect on specific prostaglandins like PGE1 or totally block prostaglan -
din biosynthesis, including PGI2 and thromboxane A2.22 Blocking thromboxane A2 
myocardial receptors could prevent MI and sudden cardiac death.150
By contrast, one in vitro  study that examined the effect of DMSO on PGI2 synthe -
sis concluded that DMSO suppressed PGI2 production in cultured aortic endothelial 
cells by interfering with the release of arachidonic acid in the prostaglandin cascade. This study did not investigate what action, if any, DMSO might have exerted on thromboxane A
2 production since a high dose of DMSO, like aspirin, would inhibit 
not only PGI2 but also thromboxane synthesis by blocking the COX-1 arachidonic 
acid pathway. In a recent study by Asmis et al.,151 this is precisely what DMSO appears to do. The incubation of platelet-rich plasma with DMSO 0.5% (6.3 Mm) for 30 min sig -
nificantly decreased total COX-1 activity by 36% compared to control. When DMSO 68 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
was compared to the COX-1-specific inhibitor SC-560, a similar inhibition of 33% 
of total COX activity was observed with SC-560 as compared to control.151 When 
DMSO and SC-560 were combined , no further reduction in COX-1 activity was seen, 
an indication that the residual COX-2 activity was not inhibited by either agent and that DMSO acted as a selective inhibitor of COX-1. 151 This is an important find -
ing because the inhibition of COX-2 by some NSAIDs has been associated with an increased risk of renal failure, heart attack, thrombosis, and stroke through an increase in thromboxane A
2, which reduces the synthesis of PGI2.152,153
In the study by Asmis et al.,151 when the exogenous thromboxane A2 analogue 
U46619 was combined with DMSO, the inhibitory effect of DMSO on platelet aggre -
gation was prevented, implying that DMSO has the ability to block the prothrom -
botic release of thromboxane A2. The collective evidence from all these studies is that DMSO, like aspirin, is an 
antiplatelet agent with unique activities in blocking prostaglandin biosynthesis and the production of the powerful platelet aggregator thromboxane A
2, a cornerstone of 
acute coronary syndrome and stroke prevention. Like aspirin, whose optimal oral dose is recommended to be not greater than 75–81 mg/day, DMSO is in need of a clinical study that establishes its optimal dose and route of administration so it can best serve as a long-term antiplatelet agent in the control and prevention of acute coronary syndromes and stroke. The data presented here on the effects of DMSO as a treatment for coronary 
stenosis and cardiac ischemia strongly suggest that this drug could be an effective anticlot-forming, cardioprotective, and stroke-preventing agent with similar actions as aspirin but void of the potential side effects such as hemorrhage, gastric pain, nausea, and skin rashes often seen with aspirin. TISSUE FACTOR AND INFLAMMATION
The third and fourth properties expressed by DMSO as a potential antithrombotic agent are its inhibition of tissue factor expression and its anti-inflammatory activity. Atherothrombotic vascular disorders often underlie CAD, stroke, and peripheral 
arterial disease and involve coagulation-induced thrombogenic molecules that can generate inflammatory reactions. In the coagulation cascade, thrombin promotes platelet adhesion and aggregation 
by activating protease-activated receptors on the cell membrane of the platelet. 154
Because thrombin plays a central role in arterial thrombogenesis, the goal of most 
treatment regimens is to block thrombin generation or inhibit its activity. Direct thrombin inhibitors are a new class of anticoagulants that are used to pre -
vent arterial or venous thrombosis. By reducing the bound thrombin activation of platelets, direct thrombin inhibitors can also be used as antiplatelet agents for such conditions as acute coronary syndromes and stroke. 155 They act by inactivating free 
thrombin or the thrombin that is bound to fibrin.155
Inactivation of fibrin-bound thrombin can be achieved by blocking upstream mol -
ecules in the coagulation cascade such as tissue factor. This approach is as effective as direct thrombin inhibition in preventing thrombin-induced platelet aggregation. 15469 DMSO Clinical Pharmacology
Tissue factor is a cell surface glycoprotein that interacts with plasma factor VIIa 
to activate the coagulation cascade and generate thrombin in a stepwise activation of 
a series of proenzymes.156
The best known function of tissue factor is its role in blood coagulation where 
together with factor VIIa it forms a common pathway that leads to the formation of thrombin. 157
Thrombin plays a dual action role where it normally contributes to signaling 
platelets for hemostasis and, abnormally, where it triggers platelet activation and arterial thrombosis that can result in heart attacks and stroke. 158 Thrombin has a 
large array of functions, but its primary role is the conversion of fibrinogen to fibrin, the primary building block of a hemostatic plug. 159,160 Although tissue factor is essen -
tial for hemostasis, its aberrant upregulation can also lead to atherothrombosis via the formation of thrombin. The exact role of tissue factor in thrombosis remains unclear, but it has been 
found present in atherosclerotic plaques, and recent studies suggest that tissue 
 factor–positive microparticles are the most abundant source in plaques.161
Rupture of high-risk vulnerable plaques with the subsequent tissue factor expo -
sure is responsible for coronary thrombosis, acute MI, and sudden cardiac death.162,163 
Moreover, plaque thrombogenicity is directly correlated to the presence of elevated tissue factor content. 164 When a plaque ruptures, tissue factor on the plaque surface 
triggers thrombus formation, leading to downstream arterial occlusion.165
Thrombosis and inflammation are two major consequences of blood coagulation, 
and both can promote each other. Tissue factor can induce both thrombosis and inflammation through coagulant mediators factor VIIa, factor Xa, and fibrin produc -
tion, all of which are proinflammatory. 166
It would seem that if a drug could be found that suppressed tissue factor, vul -
nerable atherosclerotic plaque formation and platelet activation leading to arterial thrombosis could be dampened and possibly prevented. Emerging evidence in a key research finding by Camici et  al . 167showed that 
DMSO was able to suppress tissue factor expression and activity as well as thrombus formation in a mouse carotid artery injury model. Tissue factor expression was seen to increase 19- and 24-fold in human aortic endothelial cells stimulated with tissue necrosis factor-a (TNF- α) or thrombin, respectively. 167 What was remarkable about 
this study was that DMSO was seen to inhibit the tissue factor induction of TNF- α 
and thrombin in a concentration-dependent manner. In the same study, in addition to blocking tissue factor mRNA expression, DMSO also inhibited the proliferation and migration of vascular smooth muscle cells, which occurs in vascular injury and atherogenesis after signal transduction pathways are activated. 168 No toxic effects by 
DMSO on the aortic endothelial cells were observed even at the highest doses used of 12.6 mmol/L,
157a finding previously supported in human corneal endothelial cells.169 
The findings from this study prompted the suggestion that DMSO has the potential to be applied to drug-eluting stents in order to inhibit platelet aggregation, particu -
larly since DMSO was also shown to suppress paclitaxel- and rapamycin-induced tissue factor expression, which are known to represent a cause for stent thrombosis in drug-eluting stents. 170,17170 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
DMSO was found to suppress in a concentration-dependent manner tissue factor 
expression and activity in response to TNF- α or thrombin exposure in human endo -
thelial cells, monocytes, and vascular smooth muscle cells in vitro .167 Moreover, it 
was additionally observed that DMSO prevented the proliferation and migration of 
vascular smooth muscle cells from human aorta, an outcome that could have impor -
tant clinical application in treating coronary thrombosis and MI.167
In summary, DMSO combines antiplatelet and anti-inflammatory properties 
much like aspirin, a drug of choice for the prevention of cardiovascular disease and stroke,
172 but unlike aspirin, DMSO adds two more properties that can additionally 
block alternate signaling pathways that lead to coronary artery syndromes. These two additional properties, anti-free radical effect on platelet aggregation
173,174 and 
anti thrombin activity on thromboembolism,151,167 place DMSO in a class by itself as 
a potential treatment for thrombogenesis of any etiology. Clinical studies to investigate these actions by DMSO seem highly warranted. CLINICAL TOXICOLOGY
The DMSO toxicology in animals is discussed in Chapter 2. A thorough human toxi -
cology study was reported by Brobyn5 in 1967 due to the wide and ever-increasing 
use of DMSO not only under clinical supervision but also as a home remedy where DMSO could be purchased over the counter by consumers. A short-term study (14 days) and a long-term study (90 days) were undertaken by 
Brobyn,
5 who reported his findings on 213 healthy human volunteers. These volun-
teers were periodically examined by specialists after being administered 1 g/kg/day 80% DMSO daily. This dose was considered 3–30 times higher than the typical DMSO dose used or recommended. The specific clinical examinations included complete physical examinations with laboratory examinations of blood and urine, ophthalmologic, dermatologic, cardiologic, neurologic, pulmonary function, and bone marrow studies. 5
The results of this study concluded that no significant adverse effects from either 
the short-term or long-term administration of DMSO were observed after a very extensive toxicology study was conducted. 5 Minor side effects of DMSO adminis -
tered daily included skin irritation, nausea, sedation, and diarrhea, which resolved following discontinuation of DMSO. 5 DMSO at 3–30 times the usual treatment dose 
in humans appeared as a relatively very safe drug, and in particular, no lens changes that were seen to occur in some animal species were detected in any subject after extensive ophthalmological examinations after 3-month follow-up. 5 This absence of 
ocular changes after high and prolonged administration of DMSO has been fully confirmed in other studies. 175–177 There has not been another major toxicological 
study on topical DMSO following Brobyn’s5 report, but thousands of papers deal -
ing with DMSO and its various routes administration, including intravenous, oral, dermal, and intravesical, have reported that adverse reactions are relatively mild and 
usually can occur in relation to its concentration and its mode of administration. 177–179
Following intravenous administration, the best-documented side effect from 
DMSO is intravascular hemolysis after intravenous infusion of 40% solution 
or greater, which can result in urinary excretion of hemoglobin.180 Dark urine is 71 DMSO Clinical Pharmacology
sometimes a marker of kidney damage, but despite a dose-dependent transient hemo -
lysis with resultant hemoglobinuria, no injury or alteration of renal function after 
DMSO administration occurs.181 The hemolysis appears related to osmotic changes 
exerted by DMSO on erythrocytes. In one case report, 50 mL intravesical instil -
lation of 50% DMSO was used successfully to stop chronic, profuse hematuria due to eosinophilic cystitis, a condition characterized by dysuria, frequency, and hematuria. 182
Intravascular hemolysis by DMSO after intravenous administration can be pre -
vented by using less than a 30% DMSO solution.178 However, in order to avoid fluid 
overload and hypernatremia, DMSO should not be given at highly diluted rates of infusion, that is, 10% or less. 183 Fluid overload can be avoided if the DMSO solution 
is infused between 25% and 35% concentration.184,185
An annoying side effect of DMSO administration by any route includes a 
 garlic-like breath odor due to the pulmonary excretion of its breakdown product to 
dimethyl sulfide.179 This odor produced from DMSO can potentially interfere with 
double-blinded clinical trials when intravenous or topical DMSO is used because the sulfide odor will easily identify the patient receiving this treatment. However, the odor problem caused by DMSO administration can be neutralized with scouting equipment placed in the room that absorbs the dimethyl sulfide and maintains the room relatively odor free. DMSO is a relatively safe drug. Side effects to DMSO are common, but these are 
usually minor and are related to the concentration of DMSO used and the route of administration. 186–188
REFERENCES
 1. Jacob SW, Bischel M, Herschler RJ. Dimethyl sulfoxide (DMSO): A new concept in 
pharmacotherapy. Curr Ther Res Clin Exp . 1964;6:134–135. 2. F orouzanfar T, Kemler M, Kessels AG, Köke AJ, van Kleef M, Weber WE. Comparison 
of multiple against single pain intensity measurements in complex regional pain syn -
drome type I: Analysis of 54 patients. Clin J Pain . 2002;18(4):234–237. 3. T ran de QH, Duong S, Bertini P, Finlayson RJ. Treatment of complex regional pain 
syndrome: A review of the evidence. Can J Anaesth . 2010;57:149–166. 4. Perez RS, Zuurmond WW, Bezemer PD, Kuik DJ, van Loenen AC, de Lange JJ, Zuidhof 
AJ. The treatment of complex regional pain syndrome type I with free radical scaven -
gers: A randomized controlled study. Pain . 2003;102(3):297–307. 5. Brobyn RD. The human toxicology of dimethyl sulfoxide. Ann N Y Acad Sci . 1975;243:497–506. 6. Rok yta R, Fricová J. Ontogeny of the pain. Physiol Res . 2012;61(Suppl 1):S109–S122. 7. Schaible HG. Peripheral and central mechanisms of pain generation. Handb Exp 
Pharmacol. 2007;177:3–28. 8. Cerv ero F. Sensory innervation of the viscera: Peripheral basis of visceral pain. Physiol 
Rev. 1994;74(1):95–138. 9. McMahon SB. Mechanisms of cutaneous, deep and visceral pain. In Textbook of Pain , 
3rd edn, eds. P.D. Wall and R. Melzack, Churchill Livingstone, Edinburgh, U.K., 1994; 
pp. 128–153. 10. Bur gess PR, Perl FR. Myelinated afferent fibres responding specifically to noxious stim -
ulation of the skin. J Physiol . 1967;190:541–562.72 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
 11. K err FWL. Neuroanatomical substrates of nociception in the spinal cord. Pain. 1975;1:325–356. 12. Clark D, Hughes J, Gasser HS. Afferent function in the group of nerve fibers of slowest 
conduction velocity. Am J Physiol . 1935;114:69–76. 13. Collins WF, Nulsen FE, Randt CT. Relation of peripheral nerve fiber size and sensation 
in man. Arch Neurol . 1960;3:381–385. 14. T orebjork HE, Hallin RG. Perceptual changes accompanying controlled preferen -
tial blocking of A and C fibre responses in intact human skin nerves. Exp Brain Res . 1973;16:321–332. 15. Murinson BB, Griffin JW . C-fiber structure varies with location in peripheral nerve. J Neuropathol Exp Neurol. 2004;63(3):246–254. 16. Craig KD, Weiss SM. Vicarious influences on pain-threshold determinations. J Pers Soc 
Psychol . 1971;19:53–59. 17. Dw orkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso 
EA et al. Recommendations for the pharmacological management of neuropathic pain: 
An overview and literature update. Mayo Clin Proc . 2010;85(3 Suppl):S3–S14. 18. Acquadro C, Berzon R, Dubois D, Leidy NK, Marquis P , Revicki D, Rothman M; PRO 
Harmonization Group. Incorporating the patient’s perspective into drug development 
and communication: An ad hoc task force report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February 
16, 2001. Value Health . 2003;6(5):522–531. 19. F orouzanfar T, Koke A, van Kleef M, Weber W. Treatment of complex regional pain 
syndrome type 1. Eur J Pain . 2002;6:105–122. 20. Beecher HK. The powerful placebo. J Am Med Assoc. 1955;159(17):1602–1606. 21. Colloca L, Miller FG. The nocebo effect and its relevance for clinical practice. Psychosom Med. 2011;73(7):598–603. 22. P anganamala RV , Sharma HM, Heikkila RE, Geer JC, Cornwell DG. Role of hydroxyl 
radical scavengers dimethyl sulfoxide, alcohols and methional in the inhibition of pros -
taglandin biosynthesis. Prostaglandins . 1976;11(4):599–607. 23. Ev ans MS, Reid KH, Sharp JB Jr. Dimethylsulfoxide (DMSO) blocks conduc -
tion in peripheral nerve C fibers: A possible mechanism of analgesia. Neurosci Lett. 1993;150(2):145–148. 24. Funk CD . Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science. 2001;294:1871–1875. 25. Dugg an JM. Aspirin ingestion and perforated peptic ulcer. Gut. 1972;13(8):631–633. 26. Beck er DP, Young HF, Nulsen FE, Jane JA. Physiological effects of dimethyl sulfoxide 
on peripheral nerves: Possible role in pain relief. Exp Neurol . 1969;24(2):272–276. 27. P aul MM. Interval therapy with dimethyl sulfoxide. Ann N Y Acad Sci . 1967;141(1):586–598. 28. Lockie LM, Norcross BM. A clinical study on the effects of dimethyl sulfoxide in 103 
patients with acute and chronic musculoskeletal injuries and inflammations. Ann N Y 
Acad Sci . 1967;141(1):599–602. 29. Blumenthal LS, Fuchs M. The clinical use of dimethyl sulfoxide on various head -
aches, musculoskeletal, and other general medical disorders. Ann N Y Acad Sci . 1967;141(1):572–585. 30. Kneer W, Kühnau S, Bias P, Haag RF. Dimethylsulfoxide (DMSO) gel in treatment of 
acute tendopathies. A multicenter, placebo-controlled, randomized study. Fortschr Med . 1994;112(10):142–146. 31. Matsumoto J. Clinical trials of dimeth yl sulfoxide in rheumatoid arthritis patients in 
Japan. Ann N Y Acad Sci . 1967;141(1):560–568. 32. Penrod DS, Bacharach B, Templeton JY . Dimethyl sulfoxide for incisional pain after 
thoracotomy: Preliminary report. Ann N Y Acad Sci . 1967;141(1):493–495.73 DMSO Clinical Pharmacology
 33. Asen H. Dimeth yl sulfoxide: A new concept in the treatment of ENT diseases. Ann N Y 
Acad Sci . 1967;141(1):451–457. 34. Perc y EC, Carson JD. The use of DMSO in tennis elbow and rotator cuff tendonitis: 
A double-blind study. Med Sci Sports Exerc. 1981;13(4):215–219. 35. Freeman GR. DMSO in otology . Laryngoscope . 1976;86(7):921–929. 36. Chung O Y , Bruehl S. Complex regional pain syndrome. Curr Treat Options Neurol. 2003;5:499–511. 37. Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology . 2010;113(3):713–725. 38. Harden RN, Bruehl S, Galer BS, Saltz S, Bertram M, Back onja M, Gayles R, Rudin N, 
Bughra M, Stanton-Hicks M. Complex regional pain syndrome: Are the IASP diagnos-
tic criteria valid and sufficiently comprehensive? Pain. 1999;83:211–219. 39. P arkitny L, McAuley JH, Di Pietro F, Stanton TR, O’Connell NE, Marinus J, van Hilten 
JJ, Moseley GL. Inflammation in complex regional pain syndrome: A systematic review and meta-analysis. Neurology. 2013;80(1):106–117. 40. Ale xander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ. Changes in 
cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain 2005;116:213–219. 41. Maihofner C, Handwerk er HO, Neundörfer B, Birklein F. Mechanical hyperalgesia in 
complex regional pain syndrome: A role for TNF-alpha? Neurology 2005;65:311–313. 42. Schink el C, Gaertner A, Zaspel J, Zedler S, Faist E, Schuermann M. Inflammatory medi -
ators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain .
Dimethyl_Sulfoxide_(DMSO)_in_Trauma_and_Disease_[2015].txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

        Excellent and dramatic results with complete remission of symptoms were achieved in 28 cases, and marked improvement was observed in 52 cases, while 22 cases remained unimproved. Many of the patients treated with DMSO had been refractory to cortisone and antibiotic creams. A distinctly longer-lasting effect could be achieved when antibiotics such as tetracycline and erythromy -
cin dissolved in DMSO were applied. 33
Not all studies using topical DMSO for rotator cuff and tendinitis pain showed 
positive results. In a year-long study involving 102 patients presenting with either medial or lateral epicondylitis (tennis elbow) or rotator cuff tendonitis were treated with topical applications of DMSO. Beneficial effects were assessed with respect to improvement in pain, tenderness or swelling, and increase in the range of motion. Forty patients treated with topical 70% DMSO aqueous solution did not report any more benefit from the drug than patients who received a 5% DMSO aqueous placebo solution. 34
A review of DMSO in otological conditions by Freeman35 in 1976 claimed that a 
thorough review by him of the literature revealed no evidence that topical application of the drug was useful and concluded that although DMSO was not ototoxic, double-blind studies on patients with otological infections demonstrated that 90% DMSO 54 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
applied within the external auditory canal had no anti-inflammatory, antibacterial, 
or analgesic properties, and there was no evidence that it potentiated the action of other medicines when mixed preparations were used. To support this conclusion, Freeman
35 cited 11 references in his review, most of which in fact supported the 
opposite conclusion from that derived by Freeman,35 who referred to “many double-
blind studies” that demonstrated the lack of activity by DMSO but never once cited any of these reports or references. Such shoddy and scientifically lazy conclusions failing to cite any report in sup -
port of its tenet would haunt DMSO for years as the shroud of its mystique and sometimes enthusiastic hyperbole by its supporters grew exponentially to the degree of putting into question the credibility of many evidence-based and well-performed experiments, both basic and clinical, that showed either positive or negative findings for the actions of this molecule on a variety of models and systems. Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic 
dystrophy and causalgia, is a chronic systemic disease characterized by intense neu -
ropathic pain out of proportion to the severity of the injury. 36 CRPS can result from 
even a mild tissue trauma to an extremity, and when it does, it is typically character -
ized by swelling and severe pain of the extremity and by dramatic color and tempera -
ture skin changes. 37 There is no specific test that can diagnose CRPS, and diagnosis 
is often made by the exclusion of similar pain conditions. CRPS is divided into two types: CRPS-1, which lacks demonstrable nerve lesions, 
and CRPS-2, formerly known as causalgia, where the pain is generally neuropathic and more severe than type 1 and where evidence of nerve damage is present. 38
The specific cause of CRPS is not known for certain, but dysfunction or damage 
to the peripheral or central nervous system (CNS) may follow a nerve injury after trauma or surgery. 39
Another theory is that CRPS is caused by an immune response that leads to the 
changes seen in the skin (redness, warmth, swelling, and pain) involving proin-flammatory mediators such as TNF-alpha, interleukins 1 β, 2, 6, 8, and C-reactive 
 protein,40–42 as well as increased systemic levels of proinflammatory neuropep -
tides, including substance P and bradykinin. 43 Other findings indicate that when 
there are no clinical signs of peripheral nerve damage, posttraumatic focal CRPS-1 is nonetheless associated with significant loss of C-fibers and A- δ fibers in the 
affected area. 44
About 50,000 new cases of CRPS are estimated to occur annually in the United 
States alone (Bruehl), generally following surgery, simple fractures, crush injuries, and sprains. 38 When a limb is affected, loss of strength and decreased active range of 
motion can disable the individual, resulting in continuous intense pain and psycho -
logical stress. In fact, the pain can be so intense in CRPS that it has the unfortunate honor of being described as the most painful syndrome or disease, scoring highest on the McGill pain scale (42 out of a possible 50), and considerably above such events as amputation of a digit and childbirth (see Figure 3. 1). After many randomized-controlled trials published, there is no clinical consensus 
on how to treat or manage CRPS. 45
Pathophysiologically, oxidative damage by free radicals have been implicated in 
the development of CRPS. 46 In addition, pain sensation that increases with time, 55 DMSO Clinical Pharmacology
also called wind-up, and CNS sensitization are important neurologic processes that 
have been reported to be involved in the unfolding of CRPS. 47 In this regard, it is 
interesting to note that elevated CNS glutamate levels promote wind-up and CNS 
sensitization. 47
In addition, there is experimental evidence that demonstrates that N-methyl- d-
aspartate (NMDA) receptors are localized in peripheral nerves and appear to be activated following CRPS. 48 Moreover, there is compelling evidence that the NMDA 
receptor has significant association in the CNS sensitization process involving CRPS. 49 This finding has led to the use of NMDA receptor blockers and free radical 
scavengers as a primary target for neuropathic pain48 that can lead to central sensiti -
zation and wind-up  phenomena such as that seen in CRPS. 50
Good to excellent results in pain control of patients with CRPS type 1 have 
been shown after the topical application of 50% DMSO over the affected area. 51 
The results indicated significantly favorable pain management, particularly when the CRPS was associated with inflammatory symptoms. 51 The mechanism by which 
DMSO is able to provide pain relief in one of the most difficult to treat pain condi -
tions remains unclear. A clue may lie in the fact that DMSO acts as a powerful free radical scavenger, 
and it is well known that free radicals following injury can be toxic to tissue and introduce acute or chronic pain sensation. DMSO is also an NMDA and glutamate receptor antagonist, and both substances can activate hyperalgesia and neuropathic pain. CRPS
Amputation of dig it50
40
30
20
10
0Chronic back pain
Phantom limb painChildbir th pr imipara
Childbir th multipara
Nonterminal cancer
Fracture
FIGURE 3. 1  The McGill Pain Index is a subjective measure used clinically to compare 
pain perception from 0 to 50 in patients and provide a guideline for analgesic efficacy. CRPS 
is nearly at the 50-point mark, the highest pain sensation felt by humans. The analgesic least likely to do harm and provide good efficacy in the treatment of CRPS was reported to be DMSO. (From Quisel, A. et al. , J. Fam. Pract. , 54(7), 599, 2005. )56 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
One of the cardinal features of inflammatory states is that normally innocent 
stimuli can produce severe pain. This may be one of the mechanisms targeted by 
DMSO as an anti-inflammatory agent. Finally, DMSO has the ability to block C-fiber and small fiber pain fibers after its topical application. These actions may explain to some degree the number of studies that have tested DMSO in hundreds of patients where controlling pain and the consequences of CRPS were achieved. 23,26,51–53
To compare the effects of two free radical scavengers, topical 50% DMSO and 
N-acetylcysteine (NAC) were used for the treatment of CRPS-1, in a randomized, 
double-dummy controlled, double-blind trial. 3 Treatments were conducted in 146 
patients over a period of 24 months. Patients were randomized into two treatment groups: one was instructed to apply DMSO 50% five times daily to the affected extremity, and the second was treated with NAC 600 mg effervescent tablets three times daily, and both treatments were compared to each other and to a placebo. Significant differences were found for subscores of lower extremity function, in favor of DMSO treatment. 3 Subgroup analysis showed more favorable results for DMSO 
for warm CRPS-1 than for NAC. 3
A study by Gaspar et al. 54 evaluated the topical treatment of 50% DMSO cream 
in type 1 CRPS over a period of 15 days, 1 month, 3 months, 6 months, and 1 year in 29 patients. The evaluation was performed using primarily a visual analogue scale (VAS) as the main efficacy variable that measures the patient’s pain intensity subjectively. Secondary measures of efficacy by DMSO included the quality of life after treatment and the physical mobility of the affected limbs, involving range of motion, strength, and overall limb function. The results showed that topical appli -
cation of 50% DMSO significantly diminished pain intensity approaching absence of pain, according to the VAS score at each period of observation. Secondary measures of efficacy were also recorded as higher scores on the quality of life questionnaire with a general improvement on limb rigidity, mobility, and func -
tion. 54 Thus, this study by Gaspar and his team54 complies with the QFW values  
for the quality of easing pain (Q), restoring or significantly improving anatomic–physiological function (F), and general well-being (W) expressed by the patients following treatment. One of the first studies to recognize the usefulness of DMSO in the treatment 
of CRPS was reported by Goris
55 in 1985. Goris55 showed that DMSO as an anti-  
inflammatory and free radical scavenger agent could reduce the inflammation 
 associated with CRPS and demonstrated, in an open study, a reduction of the CRPS 
symptoms using 50% DMSO cream. These results led to a prospective,  r andomized, 
and double-blind study on 32 patients following an accidental trauma and the devel -
opment of acute CRPS. 56 Patients showed increased temperature,  r edness, and pain 
in the affected extremity, coupled to a limited range of motion of the limb. A VAS was used to measure the redness, swelling, and limited active range of motion of  the affected extremity. DMSO 50% cream applied five times daily was com -
pared to a placebo cream for 2 months. After 2 months, DMSO showed significant 
(p < 0. 01) improvement of the VAS measures as compared to the placebo cream, 
and the authors recommended further use of DMSO for CRPS. 56 Side effects from 
the DMSO  a pplications were mild scaling of the skin in the affected areas, which 
resolved in time. 5657 DMSO Clinical Pharmacology
More recently, topical application of 50% DMSO three to five times daily was 
given as an anti-inflammatory therapy to 74 patients with CRPS and a mean dis -
ease duration of 17 weeks. 57 The DMSO treatment was supplemented with physical 
therapy and acetaminophen as an oral analgesic. Of the 74 patients with early CRPS, 
55 (74%) patients significantly showed improvement in their pain score. Although no attempt was made to examine whether analgesia was obtained with DMSO or acetaminophen, the authors concluded that this package treatment should become standard therapy for patients presenting with early CRPS. 57
A review of the most promising treatments for CRPS-1 at the present time con-
cluded that early treatment of this syndrome is more likely to respond to treatment. 58 
Of all the therapies for CRPS considered, including a wide range of analgesics, gan -
glionic blockers, steroids, adrenoceptor antagonists, acupuncture, calcitonin, and the glutamate blocker ketamine, the authors concluded that the therapy least likely to do 
harm and supported by evidence of efficacy  was topical 50% DMSO cream
58 (see 
Figure 3.
Not mentioned in the text
What percentage of patients with CRPS type 1 showed significant improvement in their pain score after treatment with DMSO?
The primary cause of CRPS is not specified in the text, but it is mentioned that it may be associated with damage to the peripheral or central nervous system. Treatment approaches are not discussed in this passage.
What is the primary cause of CRPS, and what is the treatment approach?
The primary mechanism is not specified in the text, but it is mentioned that DMSO acts as a powerful free radical scavenger and an NMDA receptor antagonist.
What is the primary mechanism by which DMSO provides pain relief in CRPS?
Not mentioned in the text
What is the conclusion of the study by Pestronk and Drachman regarding the use of DMSO as an anti-inflammatory agent?
The primary advantage of using DMSO is not specified in the text, but it is mentioned that it reduces inflammation and can be used to treat IC.
What is the primary advantage of using DMSO in the treatment of IC, and what are the potential side effects?