Dimethyl Sulfoxide (DMSO) in Orthopedic Practice: An Evidence-Based Protocol
Table of Contents
1. Pharmacology: Established and Hypothetical
1.1. Structure and physicochemical properties
DMSO is a low-molecular-weight (78 Da) dipolar aprotic compound. Through hydrogen bonding with water and its amphiphilic character, it readily traverses the intact stratum corneum, phospholipid membranes, and collagen structures.
1.2. Mechanisms of action
Established in vivo:
- Penetration enhancement — facilitates transcutaneous transport of dissolved compounds; the principal clinically relevant effect.
- Antioxidant activity — scavenges hydroxyl radicals (•OH); reduces local oxidative stress.
- Local vasodilation with increased perivascular perfusion.
Demonstrated primarily in preclinical models (in vitro, animal studies):
- Downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) via NF-κB-dependent pathways.
- Stabilization of inflammatory cell membranes.
- Suppression of conduction in unmyelinated C-fibers (analgesic component).
Direct clinical extrapolation of preclinical mechanisms to therapeutic efficacy in humans remains an open question.
1.3. Metabolism and elimination
DMSO is hepatically metabolized via two pathways: oxidation to dimethyl sulfone (renal elimination) and reduction to dimethyl sulfide — eliminated via respiratory and cutaneous routes, accounting for the characteristic garlic-like odor. Plasma T½ is approximately 11–20 hours. In hepatic or renal impairment, metabolism and elimination are slowed.
2. Regulatory Status
| Jurisdiction | Status |
|---|---|
| United States (FDA) | Approved: intravesical instillation for interstitial cystitis (RIMSO-50). Musculoskeletal indication exists only as a component of Pennsaid (diclofenac sodium 1.5–2% in a 45.5% DMSO vehicle) for knee osteoarthritis. |
| European Union (EMA) | Pennsaid is approved. No monoproduct of DMSO is registered for musculoskeletal use. |
| Eastern Europe / CIS | Registered as a topical concentrate (50–99%) under brand names such as Dimexide. Indication: inflammatory and post-traumatic musculoskeletal conditions. Adults only. |
No major contemporary guideline (EULAR 2023, OARSI 2019, ACR/AF 2019/2020) includes DMSO monotherapy in recommendations for OA, RA, or tendinopathies. Topical NSAIDs, by contrast, carry a strong recommendation for knee and hand OA.
3. Evidence Base by Indication
3.1. Osteoarthritis
The systematic review and meta-analysis by Brien S et al. (Osteoarthritis Cartilage 2008; Evid Based Complement Alternat Med 2011) analyzed four randomized controlled trials of DMSO monotherapy in knee OA (n = 297 in active treatment arms). The conclusion: no definitive evidence of efficacy of DMSO monotherapy. In the pivotal trial by Bookman AA et al. (CMAJ 2004), topical diclofenac in a 45.5% DMSO vehicle was significantly superior to the 45.5% DMSO vehicle alone, indicating DMSO's role as a penetration enhancer for NSAIDs rather than as an independent therapeutic agent.
Clinical positioning: DMSO monotherapy in OA is not recommended as standard of care. Possible use is limited to short adjuvant courses alongside core therapy (systemic or topical NSAIDs, quadriceps strengthening, weight management, physiotherapy).
Level of evidence (GRADE): low.
3.2. Acute closed soft-tissue injuries in adults
The best-supported orthopedic indication. DMSO accelerates hematoma resorption, reduces local exudation, and attenuates pain. Application should begin 24–48 hours after injury, after the acute vasoconstrictive phase has resolved (the first 24 hours are managed via the PRICE/POLICE protocol).
Level of evidence: low to moderate (expert opinion, historical observational series).
3.3. Tendinopathies, bursitis, and enthesopathies in adults
An acceptable short-term adjuvant in combination with eccentric loading, relative rest, load correction, and topical/systemic NSAIDs. It is not a substitute for the core rehabilitation program.
Level of evidence: low.
3.4. Postoperative edema and pain
Application is permissible only after complete epithelialization of the surgical wound (typically ≥ 14 days post-op), away from the incision line, for adjuvant control of periwound soft-tissue swelling. Early application (< 14 days) adjacent to the suture line is not recommended due to the risk of hydration stress at the wound edges and local vasodilation that may compromise coagulation hemostasis.
Level of evidence: very low.
3.5. Rheumatoid arthritis
Topical DMSO is not included in any current guideline (EULAR, ACR) for the treatment of RA. In no form may it replace disease-modifying therapy (sDMARDs, bDMARDs, tsDMARDs). Permissible use is restricted to symptomatic short-term adjuvant therapy in a patient already receiving adequate core treatment, without modification of its dosing or regimen.
3.6. Conditions in which DMSO should NOT be used in orthopedics
- Patients under 18 years of age (absence of safety and efficacy data).
- Acute inflammatory arthritis of any etiology without a verified diagnosis.
- Septic arthritis, osteomyelitis, infected wounds.
- Active crystal arthropathy.
- Conditions requiring urgent surgical intervention.
4. Standardized Application Protocol for Adults
4.1. Working solution preparation
Pharmaceutical-grade DMSO (99% concentrate) is diluted with sterile 0.9% sodium chloride or boiled cooled water.
| Concentration | DMSO : diluent ratio | Working indication |
|---|---|---|
| 25% | 1 : 3 | Sensitive skin; initial use; elderly patients |
| 30% | 1 : 2.3 | Most standard indications (OA, contusions, tendinopathies) |
| 50% | 1 : 1 | Deep tendinopathies, marked post-traumatic edema |
Concentrations below 10% are empirically considered clinically inactive. Concentrations exceeding 50% for cutaneous application do not provide additional clinical benefit and substantially increase the risk of local toxicity and systemic absorption.
Solutions should be prepared immediately before application. Storage of the diluted product is limited to 24 hours at +4 °C in glass (not plastic) containers.
4.2. Application technique
- Sensitivity test before the first course: apply 0.5 mL of the prepared solution to a 2×2 cm area on the flexor surface of the forearm; assess at 30 minutes and 24 hours. The application is contraindicated if erythema > 5 mm, burning, swelling, or rash develops.
- Skin preparation: cleanse with neutral soap and dry. The skin must be intact — no irritation, rash, burns, excoriations, or open wounds.
- Application: a 4–8 layer gauze pad soaked with 10–20 mL of the prepared solution (without excessive dripping) is placed over the projection of the affected area.
- Fixation: only dry gauze dressing or a light elastic bandage. Polyethylene films and other occlusive materials must not be used — occlusion increases systemic absorption 5- to 10-fold and substantially raises the risk of local chemical burns.
- Exposure time:
- 25% solution — up to 20 minutes;
- 30% solution — 15–20 minutes;
- 50% solution — no more than 15 minutes.
- Removal: remove the gauze and blot the skin dry. Do not rinse the skin with water for 30 minutes (this prevents rebound local irritation).
- Frequency: 1–2 times daily.
- Course duration: 7–14 days. Courses exceeding 14 days provide no additional clinical benefit; local skin tolerance declines and the risk of contact dermatitis increases.
4.3. What NOT to do
- Do not mix with lidocaine, procaine, or other local anesthetics. DMSO sharply increases systemic absorption of the anesthetic, creating a risk of LAST (Local Anesthetic Systemic Toxicity) — neurological (perioral numbness, tremor, seizures) and cardiovascular (bradyarrhythmias, hypotension, asystole).
- Do not combine with topical corticosteroids without medical supervision — risk of systemic corticosteroid effects.
- Do not apply polyethylene film, plastic wrap, or any occlusive material.
- Do not apply to damaged skin, mucous membranes, open wounds, or fresh post-surgical suture lines.
- Do not use concentrations above 50% for cutaneous application.
- Do not use in patients under 18 years of age.
4.4. Combination with other topical agents
If additional analgesic or anti-inflammatory action is required, use registered ready-made formulations with established pharmacokinetics:
- Topical NSAIDs — diclofenac gel 1–2%, ketoprofen gel 2.5%, ibuprofen gel 5%; apply at a different time of day, without overlapping DMSO application sites.
- Topical capsaicin 0.025–0.075% — for chronic pain syndromes.
Improvised pharmaceutical mixtures of DMSO with injectable solutions (lidocaine, hydrocortisone, diclofenac injection) are not recommended due to unpredictable pharmacokinetics and the regulatory status of off-label compounding.
5. Contraindications
Absolute
- Hypersensitivity to DMSO.
- Pregnancy and lactation.
- Age under 18 years.
- Severe hepatic impairment (Child-Pugh C).
- Severe renal impairment (eGFR < 30 mL/min/1.73 m²).
- Decompensated chronic heart failure (NYHA III–IV).
- Acute myocardial infarction, unstable angina.
- Ischemic or hemorrhagic stroke < 6 months ago.
- Glaucoma (systemic vasodilation may raise intraocular pressure).
- Cataract (risk of progression with prolonged use).
- Active dermatitis, eczema, or psoriasis at the application site.
- Cutaneous infections.
Relative
- Diabetes mellitus with microangiopathy or diabetic foot.
- Chronic venous insufficiency stages III–IV.
- History of atopic dermatitis.
- Concurrent vitamin-K antagonist therapy (warfarin) — theoretical potentiation.
- Concurrent sedatives, opioids, antihistamines — theoretical CNS-depressant potentiation.
6. Adverse Effects and Management
| Effect | Expected frequency | Management |
|---|---|---|
| Garlic-like breath / skin odor | > 90% (dose-dependent) | Inform the patient; no intervention needed |
| Local erythema, burning, pruritus | 10–25% | Reduce concentration or exposure time; discontinue if persistent |
| Dryness, scaling of the skin | 5–15% | Emollients at a separate time of day |
| Allergic contact dermatitis | 1–5% | Discontinue; oral antihistamines; short course of topical corticosteroid if needed |
| Systemic vasodilation, headache, hypotension | < 1% | Discontinue; monitor blood pressure |
| Hemolysis (high concentrations, large surface area) | Rare | Discontinue; complete blood count |
| Chemical burn | Rare | Discontinue; standard first- to second-degree burn care |
| Hepatotoxicity (↑ ALT/AST) | Very rare, with courses > 4 weeks | Monitor liver enzymes during extended courses |
7. DMSO Within Multimodal Orthopedic Therapy
DMSO is an adjuvant, not an alternative to core therapy. Rational multimodal schemes for typical indications:
Acute high-volume contusion or hematoma (thigh, calf, shoulder)
- 0–24 h: PRICE/POLICE — protection, relative rest, ice (15 min every 2 h), compression, elevation.
- 24–72 h: initiate DMSO 30% 1–2 times daily + paracetamol 1 g × 4 daily ± ibuprofen 400 mg × 3 daily per os (in the absence of GI or renal contraindications).
- 72 h – 7 days: continue DMSO; gradual restoration of axial loading.
- Ultrasound surveillance for hematomas > 30 mL or progressive swelling — exclude compartment syndrome, complete muscle rupture, or deep vein thrombosis.
- Escalation criteria: resting pain > 7/10, distal paresthesia, progressive swelling, loss of pulse — urgent surgical consultation.
Knee osteoarthritis with moderate flare
- Core therapy: topical diclofenac 1–2% three times daily + quadriceps strengthening program + weight management + paracetamol as needed.
- With inadequate control: short course of DMSO 30% 1–2 times daily for 10–14 days as adjuvant.
- Do not use DMSO when septic arthritis, crystal attack, or mechanical intra-articular block is suspected — these require diagnostic workup (arthrocentesis, imaging).
Lateral epicondylitis
- Eccentric loading protocol (Tyler, Curwin; 12 weeks).
- Correction of ergonomics and sporting technique.
- Topical NSAID.
- DMSO 25–30% as short-term adjuvant (≤ 14 days) during flare.
- Consider injectable therapy (PRP) if symptoms persist beyond 6 months.
8. Conclusions
- Topical DMSO is an auxiliary agent with a limited contemporary evidence base. Its clinical value lies primarily in its role as a penetration enhancer for topical NSAIDs and as a short-term adjuvant in acute closed soft-tissue injuries in adults.
- DMSO monotherapy in OA, RA, and tendinopathies cannot replace evidence-based core therapies (topical/systemic NSAIDs, DMARDs, rehabilitation programs, injectable interventions).
- Pediatric use of DMSO is not recommended due to absence of safety data and regulatory restrictions.
- Combination with local anesthetics and the use of occlusive dressings create unpredictable pharmacokinetics with risk of systemic toxicity and are not recommended.
- Safe use requires strict protocol adherence: sensitivity test → concentrations of 25–50% → exposure up to 20 minutes → course up to 14 days → compliance with the contraindication list → monitoring of local and systemic reactions.
References
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- Brien S, Prescott P, Lewith G. Meta-analysis of the related nutritional supplements DMSO and MSM in the treatment of osteoarthritis of the knee. Evid Based Complement Alternat Med. 2011;2011:528403. PMC
- Bookman AA, Williams KS, Shainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ. 2004;171(4):333–338. PubMed
- Simon LS, Grierson LM, Naseer Z, et al. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143(3):238–245. ScienceDirect
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- Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020;72(2):220–233. ACR Journals
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