Jeffrey J. Patterson

A systematic review of prolotherapy for chronic musculoskeletal pain

Objective:Prolotherapy, an injection-based treatment of chronic musculoskeletal pain, has grown in popularity and has received significant recent attention. The objective of this review is to determine the effectiveness of prolotherapy for treatment of chronic musculoskeletal pain. Data Sources:We searched Medline, PreMedline, Embase, CINAHL, and Allied and Complementary Medicine with search strategies using all current and historical names for prolotherapy and injectants. Reference sections of included articles were scanned, and content area specialists were consulted. Study Selection:All published studies involving human subjects and assessing prolotherapy were included. Main Results:Data from 34 case reports and case series and 2 nonrandomized controlled trials suggest prolotherapy is efficacious for many musculoskeletal conditions. However, results from 6 randomized controlled trials (RCTs) are conflicting. Two RCTs on osteoarthritis reported decreased pain, increased range of motion, and increased patellofemoral cartilage thickness after prolotherapy. Two RCTs on low back pain reported significant improvements in pain and disability compared with control subjects, whereas 2 did not. All studies had significant methodological limitations. Conclusions:There are limited high-quality data supporting the use of prolotherapy in the treatment of musculoskeletal pain or sport-related soft tissue injuries. Positive results compared with controls have been reported in nonrandomized and randomized controlled trials. Further investigation with high-quality randomized controlled trials with noninjection control arms in studies specific to sport-related and musculoskeletal conditions is necessary to determine the efficacy of prolotherapy.

Dextrose Prolotherapy for Knee Osteoarthritis: A Randomized Controlled Trial

PURPOSE Knee osteoarthritis is a common, debilitating chronic disease. Prolotherapy is an injection therapy for chronic musculoskeletal pain. We conducted a 3-arm, blinded (injector, assessor, injection group participants), randomized controlled trial to assess the efficacy of prolotherapy for knee osteoarthritis. METHODS Ninety adults with at least 3 months of painful knee osteoarthritis were randomized to blinded injection (dextrose prolotherapy or saline) or at-home exercise. Extra- and intra-articular injections were done at 1, 5, and 9 weeks with as-needed additional treatments at weeks 13 and 17. Exercise participants received an exercise manual and in-person instruction. Outcome measures included a composite score on the Western Ontario McMaster University Osteoarthritis Index (WOMAC; 100 points); knee pain scale (KPS; individual knee), post-procedure opioid medication use, and participant satisfaction. Intention-to-treat analysis using analysis of variance was used. RESULTS No baseline differences existed between groups. All groups reported improved composite WOMAC scores compared with baseline status (P <.01) at 52 weeks. Adjusted for sex, age, and body mass index, WOMAC scores for patients receiving dextrose prolotherapy improved more (P <.05) at 52 weeks than did scores for patients receiving saline and exercise (score change: 15.3 ± 3.5 vs 7.6 ± 3.4, and 8.2 ± 3.3 points, respectively) and exceeded the WOMAC-based minimal clinically important difference. Individual knee pain scores also improved more in the prolotherapy group (P = .05). Use of prescribed postprocedure opioid medication resulted in rapid diminution of injection-related pain. Satisfaction with prolotherapy was high. There were no adverse events. CONCLUSIONS Prolotherapy resulted in clinically meaningful sustained improvement of pain, function, and stiffness scores for knee osteoarthritis compared with blinded saline injections and at-home exercises.

Early Inflammatory Response of Knee Ligaments to Prolotherapy in a Rat Model

Prolotherapy is an alternative injection‐based therapy for chronic musculoskeletal pain. Three different proliferants, D‐glucose (dextrose), phenol‐glucose‐glycerine (P2G), and sodium morrhuate, used in prolotherapy are hypothesized to strengthen and reorganize chronically injured soft tissue and decrease pain through modulation of the inflammatory process. Our hypothesis is that commonly used prolotherapy solutions will induce inflammation (leukocyte and macrophage infiltration) in medial collateral ligaments (MCLs) compared to needlestick, saline injection, and no‐injection controls. MCLs of 84 Sprague‐ Dawley rats were injected one time at both the tibial and femoral insertions. Immunohistochemistry (IHC) was used to determine the inflammatory response at three locations (tibial and femoral insertions and midsubstance) 6, 24, and 72 h after dextrose injection compared to saline‐ and no‐injection controls and collagenase (positive control) (n = 4). qPCR was used to analyze gene expression 24 h postinjection (n = 4). Sodium morrhuate, P2G, and needlestick control were also investigated after 24 h (n = 4). In general, inflammation (CD43+, ED1+, and ED2+ cells) increased after prolotherapy injection compared to no‐injection control but did not increase consistently compared to saline and needlestick control injections. This response varied by both location and proliferant. Inflammation was observed at 6 and 24 h postinjection but was resolved by 72 h compared to no‐injection controls (p < 0.05). CD43+ leukocytes and ED2+ macrophages increased compared to needlestick and saline‐injection control, respectively, 24 h postinjection (p < 0.05). Prolotherapy injections created an inflammatory response, but this response was variable and overall, not uniformly different from that caused by saline injections or needlestick procedures.

Response of Knee Ligaments to Prolotherapy in a Rat Injury Model

Background Prolotherapy is an alternative therapy for chronic musculoskeletal injury including joint laxity. The commonly used injectant, D-glucose (dextrose), is hypothesized to improve ligament mechanics and decrease pain through an inflammatory mechanism. No study has investigated the mechanical effects of prolotherapy on stretch-injured ligaments. Hypotheses Dextrose injections will enlarge cross-sectional area, decrease laxity, strengthen, and stiffen stretch-injured medial collateral ligaments (MCLs) compared with controls. Dextrose prolotherapy will increase collagen fibril diameter and density of stretch-injured MCLs. Study Design Controlled laboratory study. Methods Twenty-four rats were bilaterally MCL stretch-injured, and the induced laxity was measured. After 2 weeks, 32 MCLs Were injected twice, 1 week apart, with either dextrose or saline control; 16 MCLs received no injection. Seven uninjured rats (14 MCLs) were additional controls. Two weeks after the second injection, ligament laxity, mechanical properties (n = 8), and collagen fibril diameter and density (n = 3) were assessed. Results The injury model created consistent ligament laxity (P < .05) that was not altered by dextrose injections. Cross-sectional area of dextrose-injected MCLs was increased 30% and 90% compared with saline and uninjured controls, respectively (P < .05). Collagen fibril diameter and density were decreased in injured ligaments compared with uninjured controls (P < .05), but collagen fibril characteristics were not different between injured groups. Conclusion Dextrose injections increased the cross-sectional area of MCLs compared with saline-injected and uninjured controls. Dextrose injections did not alter other measured properties in this model. Clinical Relevance Our results suggest that clinical improvement from prolotherapy may not result from direct effects on ligament biomechanics.

Hypertonic Dextrose Injections (Prolotherapy) for Knee Osteoarthritis: Results of a Single-Arm Uncontrolled Study with 1-Year Follow-Up

OBJECTIVE The objective of this study was to determine whether prolotherapy, an injection-based complementary treatment for chronic musculoskeletal conditions, improves pain, stiffness, and function in adults with symptomatic knee osteoarthritis (KOA) compared to baseline status. DESIGN This was a prospective, uncontrolled study with 1-year follow-up. SETTING The study was conducted in an outpatient setting. PARTICIPANTS Adults with at least 3 months of symptomatic KOA, recruited from clinical and community settings, participated in the study. INTERVENTIONS Participants received extra-articular injections of 15% dextrose and intra-articular prolotherapy injections of 25% dextrose at 1, 5, and 9 weeks, with as-needed treatments at weeks 13 and 17. OUTCOME MEASURES Primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC). Secondary outcome measure was the validated Knee Pain Scale (KPS). Tertiary outcome measure was procedure-related pain severity and participant satisfaction. RESULTS Thirty-six (36) participants (60 ± 8.7 years old, 21 female) with moderate-to-severe KOA received an average of 4.3 ± 0.7 prolotherapy injection sessions over a 17-week treatment period and reported progressively improved scores during the 52-week study on WOMAC and KPS measures. Participants reported overall WOMAC score improvement 4 weeks after the first injection session (7.6 ± 2.4 points, 17.2%), and continued to improve through the 52-week follow-up (15.9 ± 2.5 points, p<0.001, 36.1%). KPS scores improved in both injected (p<0.001) and uninjected knees (p<0.05). Prescribed low-dose opioid analgesia effectively treated procedure-related pain. Satisfaction was high and there were no adverse events. Female gender, age 46-65 years old, and body-mass index of 25 kg/m(2) or less were associated with greater improvement on the WOMAC instrument. CONCLUSIONS In adults with moderate to severe KOA, dextrose prolotherapy may result in safe, significant, sustained improvement of knee pain, function, and stiffness scores. Randomized multidisciplinary effectiveness trials including evaluation of potential disease modification are warranted to further assess the effects of prolotherapy for KOA.

Dextrose and Morrhuate Sodium Injections (Prolotherapy) for Knee Osteoarthritis: A Prospective Open-Label Trial

OBJECTIVES This study determined whether injection with hypertonic dextrose and morrhuate sodium (prolotherapy) using a pragmatic, clinically determined injection schedule for knee osteoarthritis (KOA) results in improved knee pain, function, and stiffness compared to baseline status. DESIGN This was a prospective three-arm uncontrolled study with 1-year follow-up. SETTING The setting was outpatient. PARTICIPANTS The participants were 38 adults who had at least 3 months of symptomatic KOA and who were in the control groups of a prior prolotherapy randomized controlled trial (RCT) (Prior-Control), were ineligible for the RCT (Prior-Ineligible), or were eligible but declined the RCT (Prior-Declined). INTERVENTION The injection sessions at occurred at 1, 5, and 9 weeks with as-needed treatment at weeks 13 and 17. Extra-articular injections of 15% dextrose and 5% morrhuate sodium were done at peri-articular tendon and ligament insertions. A single intra-articular injection of 6 mL 25% dextrose was performed through an inferomedial approach. OUTCOME MEASURES The primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC). The secondary outcome measure was the Knee Pain Scale and postprocedure opioid medication use and participant satisfaction. RESULTS The Prior-Declined group reported the most severe baseline WOMAC score (p=0.02). Compared to baseline status, participants in the Prior-Control group reported a score change of 12.4±3.5 points (19.5%, p=0.002). Prior-Decline and Prior-Ineligible groups improved by 19.4±7.0 (42.9%, p=0.05) and 17.8±3.9 (28.4%, p=0.008) points, respectively; 55.6% of Prior-Control, 75% of Prior-Decline, and 50% of Prior-Ineligible participants reported score improvement in excess of the 12-point minimal clinical important difference on the WOMAC measure. Postprocedure opioid medication resulted in rapid diminution of prolotherapy injection pain. Satisfaction was high and there were no adverse events. CONCLUSIONS Prolotherapy using dextrose and morrhuate sodium injections for participants with mild-to-severe KOA resulted in safe, significant, sustained improvement of WOMAC-based knee pain, function, and stiffness scores compared to baseline status.

Prolotherapy for Chronic Musculoskeletal Pain.

Publisher Summary This chapter describes prolotherapy as an effective therapy for chronic musculoskeletal pain, including low back pain, osteoarthritis and several tendinopathies. Prolotherapy is an injection technique which involves injecting irritant or sclerosing solutions known as proliferants that initiate a local healing reaction favoring anabolic processes, though its mechanism of action is not well established. It gives a brief account of the current prolotherapy use, in vitro and animal model studies and a series of case studies among others. The efficacy of prolotherapy for tendinopathies from clinical trials is investigated and includes treatment for three tendon disorders: eral epicondylosis (tennis elbow), hip adductor and Achilles tendinopathies. Prolotherapy for osteoarthritis of the knee and finger is described with patients reporting significant improvement. A brief account of the adverse effects of the therapy is given due to the safety issue of the technique especially when performed for perispinal or rib indications. These complications were mostly reported in perispinal prolotherapy for back and neck pain including cases of neurological impairment from spinal cord irritation.

Clinical and Magnetic Resonance Outcomes in a Study of Prolotherapy for Knee Osteoarthritis: Evidence for a Potential Mechanism of Action

weakness was noted in right-sided hip abduction, foot inversion, plantarflexion, and toe extension. Right medial ankle and foot arch were atrophied. Linear hyperpigmentation with associated induration was present from the medial groin down to the medial foot arch and the first toe. Setting: Sports Medicine Clinic. Results or Clinical Course: Right foot MRI revealed mild medial muscle atrophy and edema. Bilateral thigh MRI was normal. EMG study showed no foot muscle denervation. ANA and doublestranded DNA antibodies were positive. Dermatology was consulted, and a right medial thigh skin biopsy showed histopathologic evidence of morphea. Discussion: Morphea is a self-limited, localized scleroderma characterized by excessive collagen deposition, leading to dermal and subcutaneous tissue thickening. Considerable morbidity develops from growth interference, joint contractions, limb length discrepancy, and prominent atrophy. Therapy aims to reduce inflammation in early disease. Limited disease can be managed with topical or phototherapy, but disabling linear morphea requires more aggressive therapy with methotrexate, corticosteroids, or TNF-alpha inhibitors. By initiating TNF-alpha therapy for CD, our patient was unknowingly also treating undiagnosed linear morphea. Although this arrested disease progression, years of delayed diagnosis had already resulted in chronic disability. Conclusions: This case shows the importance of considering morphea in the differential diagnosis of a patient with focal atrophy, stiffness, and pain with abnormal skin findings, as earlier treatment may have altered her functional outcome.

Can Double Blinding Distort Results in Randomized Controlled Trials

To the Editor: In their randomized controlled trial that compared prolotherapy injections with corticosteroid injections for lateral epicondylosis, Carayannopoulos et al [1] made commendable efforts toward methodologic rigor. Both patients and injectors were blinded to the solution type; improvement between groups on primary and secondary outcomes was not significantly different, and the trial results reported like outcomes for these 2 injection types. However, we are concerned that overly strict adherence to one aspect of methodologic rigor (blinding) has led to the use of a nonstandard prolotherapy protocol that limited the possibility of detecting a positive relationship between prolotherapy and lateral epicondylosis, which, in turn, may have led to conclusions that do not go far enough regarding both these results and considerations for future research. The researchers acknowledge the study design dilemma; to preserve blinding, the prolotherapy group received 2 injection sets to equal to the maximum number of corticosteroid injections deemed safe. Two sets were used despite the statement that “Standard prolotherapy treatment consists of more than 2 injection sets if patients are not clinically improving” [1]. A recent review article identified a minimum of 3 injection sets as standard [2]. Even when using the limited protocol, however, prolotherapy scores for pain and quality of life were better than corticosteroid scores at all but 1 time point, a striking consistency for a study with such a small sample size. A more robust, clinically relevant prolotherapy protocol may have shown even stronger statistically significant results. The researchers concluded that prolotherapy may be an appropriate alternative to corticosteroid injection. We agree and suggest that, in light of recent data about corticosteroid injections, these limited results begin to make the case that prolotherapy could be used instead of corticosteroid injection. When the trial began, corticosteroid injections were still regarded as “standard of care” for lateral epicondylosis. However, since then, sufficient evidence has emerged to show that steroid injections result in worse long-term outcomes than other treatments for lateral epicondylosis and are no longer justifiable on ethical grounds as a control treatment in trials [3]. More generally, the study raises the broader and difficult issue for clinical trialists, that of choosing between an explanatory design and a pragmatic design. Explanatory trials, also referred to as efficacy trials, aim to run under “laboratory con-