Prolotherapy 3

State of the Art Prolotherapy Theatre

Prolotherapy 1

Sclerosant Injections to Ligaments

Prolotherapy 2

Reduces the Risk of Recurring Back Pain

Prolotherapy 4

Neural Prolotherapy

Prolotherapy Research

Authors
Dr Simon Petrides MB BS DM-SMed DO Dip Sports Med FFSEM (UK & I)
Dr John Tanner BSc MB BS FFSEM D M-S M DSMSA
Dr. Keith Bush MB BS MD (Lond) FFSEM(UK)

Introduction to Prolotherapy


Prolotherapy
has become an accepted intervention for a variety of musculoskeletal complaints, including back pain despite its controversial 60 year history and failure so far to enter mainstream practice. This is not because of the lack of research or reasonable proof of its safety and efficacy but more likely due to its development outside the NHS since the profession of Musculoskeletal Medicine is not widespread as a career pathway within the current NHS system.

Prolotherapy for back or neck pain consists of a series of injections of an irritant, usually a dextrose based compound, into the supporting intervertebral ligaments. The injection has an osmotic and chemical irritant effect and has been shown to stimulate a controlled inflammatory response. This in turn causes a release of growth factors, which stimulate a fibroblastic response resulting in thickening and augmentation of connective tissue and collagen fibres. The proven increase in tensile strength gives rise to a more stable and therefore less painful intervertebral segment, or joint.

The indication for spinal prolotherapy is for subacute/chronic/recurrent spinal/pelvic axial or referred pain. Clinical (not just radiological) instability can respond well to prolotherapy. The relevant diagnoses are numerous and diverse but centre on cases where the natural healing or spinal support mechanisms are inadequate. However it may help prevent progress to more chronic problems and may also help avoid progress to fusion surgery.

Research shows that best results for back pain are when the course of injections is accompanied by active rehabilitation and advice on self management. In those patients for whom the technique is successful, there is usually a period of greatly reduced pain and infrequent or rare attacks of back pain for several years. Pain relief should be accompanied by steadily increasing levels of activities. Some patients, especially those with back pain, may require a further course if there is a prolonged relapse. Most practitioners would agree that pain relief can last for at least 5 years.


Prolotherapy Procedure
Prolotherapy is usually performed on 3 occasions initially with 1-3 weeks between each treatment. A further course of 3 treatments is used if the first course is subjectively or objectively helpful on a VAS pain scale but the improvement is incomplete. A common proliferant solution in the UK is a 50/50 mixture of P-2-G and 1% lidocaine. P-2-G contains phenol 2%, glycerol 25% and dextrose 25%. A weaker solution that can be used is 12.5 - 25% dextrose diluted with 1% lidocaine.

The technique involves local anaesthetic to the skin, and sometimes the use of Entonox (nitrous oxide and oxygen), or intravenous sedation for anxious patients. The treatment can be performed with or without X-ray guidance, but has been performed for many years in the UK and USA without X-ray guidance and has resulted in a similarly low adverse reaction profile as for most other spinal injections.

Summary of Comments on Prolotherapy and Lumbar Fusion Research
Of the four published randomised controlled trials on prolotherapy, two show a positive benefit, albeit combined with an exercise programme and brief manipulative treatment (Ongley, Klein). The third (Yelland) shows a sustained benefit of both prolotherapy and placebo groups over 2 years to rival that of any surgical intervention. One is negative (Dechow) for the possible reasons stated in the discussion below, and it is important to note that all of these studies were performed on chronic back pain with an average duration of 7-10 years and that the patients were not highly selected.

The literature indicates that the enthusiasm for the use of this technique has endured for over half a century. Whilst it is by no means a panacea, prolotherapy offers a substantial chance for improvement. Many anecdotal cases with dramatic responses have greatly changed patients' quality of life and in some instances led to the avoidance of spinal fusion or disc replacement. Spinal fusion and disc replacement continue to generate controversy and in any event both of these interventions are far more costly with a significantly higher number of reported complications than prolotherapy.


A recent study of the compensation cases of over 725 workers who underwent spinal fusion discovered that 36% had surgical complications and 27% needed a second operation. After 2 years only 26% had returned to work, compared to 67% of controls. 76% continued opiate use after surgery, while mean opiate use increased by 41% (Nguyen T et al. Spine, 2010). Analgesic related mortality after lumbar fusion in workers’ compensation cases has been shown to be as much as 1% (Juratli SM et al. Spine, 2009). It has been demonstrated that 2 years after surgery in a study of workers’ compensation cases, 63.9% of patients were disabled, and the re-operation rate was 22% (Juratli SM et al. Spine, 2006).

“Lumbar fusion surgery for disc degeneration, disc herniation and/or radiculopathy in a workers’ compensation setting is associated with significant increase in disability, opiate use, prolonged work loss and poor return-to-work status” (Conclusion by Nguyen et al. Spine, 2010).


Whilst further good quality research may still be required, prolotherapy is a safe and useful technique in the management of certain spinal pain syndromes. It should be considered before resorting to fusion or disc replacement in view of its minimally invasive nature, cost-effectiveness and the low incidence of adverse reactions or consequent disability compared to surgery.

Keep reading for comments on individual research


Prolotherapy References and Comments

Systematic Reviews
The evidence for the efficacy of prolotherapy is becoming clearer. Systematic reviews of prolotherapy refer to two major factors which make the evaluation of studies difficult. The first is the wide variety of compounds and protocols used for the injections and the second is the presence of co-interventions in the studies which demonstrate efficacy.

Source
Rabago D, Best T, Beamsly M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clinical J Sports Med. 2005; 15(5):376–380.
Yelland MJ, Mar C, Pirozzo S, Schoene ML, Vercoe P. Prolotherapy injections for chronic low-back pain. Cochrane Database Syst Rev. 2004; (2):CD004059.
Dagenais S, Yelland M, Del Mar C, Schoene M. Prolotherapy injections for chronic low back pain. Cochrane Database Syst Rev. 2007; 2.
Dagenais S, Haldeman S, Wooley JR. Intraligamentous injection of sclerosing solutions (prolotherapy) for spinal pain: a critical review of the literature. Spine J. 2005; 5(3):310-28.

Randomised Controlled Trials on LBP
A recent Cochrane review for the treatment of chronic low back pain found 4 high quality randomized controlled trials (RCTs) investigating prolotherapy in LBP.

Ongley 1987, Klein 1993. In 2 trials when prolotherapy was used in conjunction with spinal manipulation, exercise and other treatments, the protocol reduced pain and disability. Both of these studies demonstrated a statistically significant difference in patients reporting greater than 50% reduction of pain and disability after 6 months compared to the control group. Two systematic reviews came to similar conclusions.

Yelland 2004. This large, rigorous study used glucose alone (which is anecdotally less effective than P2G) versus saline, both groups made significant and impressive improvements in pain and disability scores (41% and 36% respectively, improvement at 1 year). The authors noted that the improvement was comparable to that reported after fusion surgery in the Swedish Lumbar Spine Study. Also it would appear that trauma caused by needling itself is actually likely to be an active part of prolotherapy treatment so the saline control injection was potentially an active treatment. This could explain the similar effects.

Dechow 1999. 74 patients from outpatient waiting list with chronic LBP (average age 45, duration median 10 years) randomised to 3 weekly injections of P2G (5ml)+5ml I% lidocaine or saline with local anaesthetic. This study used P2G versus anaesthetic injections (which anecdotally can also be therapeutic) with no associated rehabilitation. There were no statistically significant differences in outcome between groups. Radiculopathy, active litigation, obesity, co-morbidity were excluded but previous back surgery (11%) and hip arthritis not excluded. 39% were on benefits and 50% unemployed. They concluded that patient selection and combination with other treatment modalities may be factors in determining treatment success. More than 20 of the patients selected by the main investigator were deemed inappropriate for the trial by the operator (Davies) with greatest clinical experience of this treatment (personal communication). No placebo effect observed whatsoever which makes any trial of an injection treatment suspect (injections tend to provoke a strong placebo response).

Source
Ongley M, Klein R, Dorman T, et al. A new approach to the treatment of chronic low back pain. Lancet. 1987; 2: 143-146.
Klein R, Eek B, DeLong W, et al. A randomized double-blind trial of dextrose-glycerine-phenol injections for chronic, low back pain. J Spinal Disord. 1993; 6: 23-33.
Yelland M, Glasziou P, Bogduk N, et al. Prolotherapy injections, saline injections, and exercises for chronic low-back pain: a randomized trial. Spine. 2003; 29: 9-16.
Dechow E, Davies R, Carr A, et al. A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology (Oxford). 1999; 38: 1255-1259.


Scientific Research - 1 of 2
Dextrose prolotherapy is an effective treatment option in patients with chronic, recalcitrant coccygodynia and should be used before undergoing coccygectomy. Randomised studies are needed to compare prolotherapy with local steroid injections or coccygectomies.

Source
Klein RG, Dorman TA, Johnson CE. Proliferant injections for low back pain: histologic changes of injected ligaments and objective measures of lumbar spine mobility before and after treatment. J Neurol Orthop Med Surg. 1989; 10: 141-144.
Cusi M, Saunders J, Hungerford B et al. The use of prolotherapy in the sacroiliac joint. Br J Sports Med. 2010; 44(2):100-4.
Liu YK, Tipton CM, Matthes RD, et al. An in situ study of the influence of a sclerosing solution in rabbit medial collateral ligaments and its junction strength. Connect Tissue Res. 1983; 11:95-102.
Centeno C. Fluoroscopically guided cervical Prolotherapy for instability with blinded pre and post radiographic reading. Pain Physician, 2005; 8(1): 67-72.
KhanSA, KumarA, VarshneyMK, TrikhaV, YadavCS, Dextrose prolotherapy for recalcitrant coccygodynia. Journal of Orthopaedic Surgery, 2008; 16(1): 27-9.

Scientific Research - 2 of 2
Injection therapy of painful enthesopathies can provide significant relief of axial pain and tenderness combined with functional improvement, even in failed back syndrome patients. Phenol-glycerol prolotherapy provides better and longer lasting relief than injection with anaesthetics alone. Prolotherapy provides over six months of relief for some patients but generally provides relief for only a few months. However, most patients who described good to excellent relief felt that the injections had been beneficial, and requested additional injections for recurrent or residual focal pain.

Source
WilkinsonHA
. Injection therapy for enthesopathies causing axial spine pain and the failed back syndrome: a single blinded, randomised and cross-over study. Pain Physician, 2005; 8(2): 167-7.


Other Reviews on Prolotherapy
Rabago D, Slattengren, A, Zgierska A. Prolotherapy in Primary Care Practice. Prim Care, 2010; 37(1):65-80.
Banks A. A Rationale for Prolotherapy. Journal of Orthopaedic Medicine, 1991; 13(3).
Schwartz R, Sagedy N. Prolotherapy: A literature review and retrospective study. J. Neurol Orthop Med Surg. 1991; 12:220-223.
Dagenais S, Mayer J, Haldeman S, Borg-Stein J. Evidence-informed management of chronic low back pain with prolotherapy. Spine J. 2008; 8(1):203-12.
Reeves K. Prolotherapy: Present and future applications in soft tissue pain and disability. Phys Med Rehab Clin North Am. 1995; 6: 917-926.
Hauser RA. Treating chronic pain with prolotherapy. Rehab Manag. 1999; 12:26-30.
Kim S, Stitik T, Foye P, Greenwald B, Campagnolo D. Critical review of prolotherapy for osteoarthritis, low back pain, and other musculoskeletal conditions: A physiatric perspective. American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists, 2004; 83(5): 379-89.


Published Audits/Case Series

Case Study 1 - Results
The one year outcomes from this audit, with 58% of patients reporting good benefit, would suggest that prolotherapy is a worthwhile intervention in those patients with confirmed sacroiliac joint pain who have failed to get long term relief from corticosteroid injection.

Source
Chakraverty R, Dias R. Audit of conservative management of chronic low back pain in a secondary care setting – Part I: Facet joint and sacroiliac joint interventions. Acupuncture in Medicine 2004; 22(4):207-213.

Case Study 2 - Results
One hundred and ninety (190) patients were treated with prolotherapy during the study period, June 1999-May 2006. Patients whose follow-up was 1 year or greater from the last treatment were included, leaving 140 patients available for data analysis. Both pain and QoL scores were significantly improved at least 1 year after the last treatment. There were no differences in outcomes as a result of age, response to xylocaine (lidocaine) injection, insurance coverage, smoking history, or gender.

This study suggests that prolotherapy using a variety of proliferants can be an effective treatment for low back pain from presumed ligamentous dysfunction for some patients when performed by a skilled practitioner.

Source
Watson J, Shay B. Treatment of chronic low back pain: A 1 year or greater follow-up. Journal of Alternative and Complementary Medicine, 2010; 16(9): 951-958.

Case Study 3 - Results
Dextrose prolotherapy appears to be a safe and effective method for treating chronic spinal pain that merits further investigation. Future studies need to consider differences in gender response rates.

Source
Hooper R; Ding M. Retrospective case series on patients with chronic spinal pain treated with dextrose prolotherapy. J Altern Complement Med. 2004; 10(4):670-674.


Recent Audits/Unpublished Data

Petrides S, (Blackberry Clinic, Milton Keynes 2010)
A recent unpublished case series running over 2 years on 17 GB International/Olympic rowers referred by Dr Lady Anne Redgrave and Dr Richard Budget (CMO Olympic games 2012) demonstrated an 88% success with 13 rowers returning soon after treatment to full training, follow up at a mean of 1 year. (2 of the rowers were not back to full training due to other injuries). Presented at British Association of Sport and Exercise Medicine Congress 2009.

Petrides S, (Blackberry Clinic, Milton Keynes 2010)
An audit of 76 patients is ongoing using a pre-injection Oswestry Disability Index score and follow up at 3 months and 1 year. Patients include high profile international and Premiership footballers.

Tanner J, (Oving Clinic, Chichester 2008/9)
Audit of 38 patients responding to prolotherapy questionnaire. 76% received 50% or more sustained pain relief.

Tanner J, (Oving Clinic, Chichester 2006/9)
Audit of 89 cases treated at The Oving Clinic by JA Tanner showed 60% achieved more than 50% pain relief at 1-3 years year follow up.

Petrides S, (Blackberry Clinic, Milton Keynes 2006)
Internal audit. 125 patients 3 year follow up. 76 questionnaires returned demonstrated 73% were helped by prolotherapy, 47% were helped by greater than 50% on a validated VAS pain scale.


‘Adverse Effect’ Survey

Conclusions
Side effects related to prolotherapy for back and neck pain, such as temporary post injection pain, stiffness, and bruising, are common and benign. Adverse events related to prolotherapy for back and neck pain are similar in nature to other widely used spinal injection procedures. Further study is needed to fully describe the adverse event profile of prolotherapy for back and neck pain.

Comment
A study investigating the adverse effects of prolotherapy found a similar profile to other injection therapies of the spine which include pain, stiffness and bruising post-injection. Some more serious side effects were noted such as pneumothorax and nerve damage but, again, no more common than other similar procedures. (Dagenais 2006) This is excluding the early published case reports in the late 50s in the USA of death, paralysis, paraplegia etc with the use of stronger, more toxic sclerosants, as opposed to the current proliferants. No serious complication since 1960 and since the use of dextrose/phenol/glycerol and dextrose alone. The side effect profile is likely to be lower in the UK than other spinal injections due to a more targeted approach to prolotherapy with fewer insertions than that used in the USA. It is also carried out under image guidance by some practitioners.

Source
Dagenais S, Ogunseitan O, Haldeman S, Wooley J, Newcomb R. Side effects and adverse events related to intraligamentous injection of sclerosing solutions (prolotherapy) for back and neck pain: A survey of practitioners. Arch Phys Med Rehabil. 2006; 87(7): 909-913.

Other References
Dagenais S, Mayer J, Haldeman S, Borg-Stein J. Evidence-informed management of chronic low back pain with prolotherapy. Spine J. 2008; 8(1):203-12.
Rabago D, Best T, Beamsley M, Patterson J. A systematic review of prolotherapy for chronic musculoskeletal pain. Clin J Sport Med. 2005; 15(5):376-80.
Rabago D. Prolotherapy for treatment of lateral epicondylosis. Am Fam Physician, 2009; 80(5):441.
Tsatsos G, Mandal R. Prolotherapy in the treatment of foot problems. J Am Podiatr Med Assoc. 2002; 92(6):366-8.
Yelland M, Sweeting K, Lyftogt J, Ng S, Scuffham P, Evans K. Prolotherapy injections and eccentric loading exercises for painful achilles tendinosis: a randomised trial. Br J Sports Med. 2009.
Mooney V. Prolotherapy at the fringe of medical care, or is it the frontier? Spine J. 2003; 3(4):253-4.
Hooper, et al. Case series on chronic whiplash related neck pain treated with intra-articular zygapophyseal joint regeneration injection therapy. Pain Physician, 2007; 10(2):313-318.
Christopher J. Centeno, MD Prolotherapy Under C-Arm Fluoroscopy. Journal of Prolotherapy, 2009; 1(4).
Royal Society of Medicine Library Search Services Team “Prolotherapy/Sclerotherapy for the Spine and Lower Back” Database(s) Searched: Medline (MEZZ): 1966 – December 2010.


Lumbar Fusion References and Comments

Nguyen, T, et al. Long-term outcomes of lumbar fusion among workers’ compensation subjects. Spine, 2010; e-pub ahead of print.
Carreon, L, et al. Clinical outcomes after posterolateral lumbar fusion in workers’ compensation patients: A case control study. Spine, 2010; 35(19):1812-7.
Magmhout-Juratli, S, et al. Lumbar fusion outcomes in Washington State Workers’ Compensation. Spine, 2006; 31(23):2715-23.
DeBerard, M, et al. Outcomes of posterolateral lumbar fusion in Utah patients receiving workers’ compensation. Spine, 2001; 26(7):738-47.
Atlas, S. Point of View, Clinical outcomes after posterolateral lumbar fusion in workers’ compensation patients: A case control study. Spine, 2010; 35(19):1818-9.
Bentsen S, Rustøen T, Wahl A, Miaskowski C. The pain experience and future expectations of chronic low back pain patients following spinal fusion. Journal of Clinical Nursing, 2008; 17(7B):153-9.

Comment
As many as 87% reported pain 1-8 years after the surgery. A high percentage of patients with CLBP continue to experience pain 1-8 years after spinal fusion.

Bentsen S, Wahl A, Strand L. Outcomes for patients with chronic low back pain treated using instrumented fusion. Scandinavian Journal of Caring Sciences, 2007; 21(1): 71-8.

Comment
16% of patients reported no pain, 17% mild pain, 29% moderate pain and 38% strong to excruciating pain following treatment using instrumented fusion (84% still in pain).

Mirza S, Deyo R. Systematic review of randomised trials comparing lumbar fusion surgery to non-operative care for treatment of chronic back pain. Spine, 2007; 32(7):816-23.

Comment
Surgery may be more efficacious than unstructured non-surgical care for chronic back pain but may not be more efficacious than structured cognitive-behaviour therapy.

Rehab as good as spinal fusion for chronic back pain. Journal of Family Practice, 2005; 54(9):752.

Robertson P, Jackson S. Prospective assessment of outcomes improvement following fusion for low back pain. Journal of Spinal Disorders & Techniques, 2004; 17(3):183-8.

Comment
Only 28.6% of patients followed achieved good or excellent low back outcome scores after fusion.

Wilson-MacDonald J. Should backache be treated with spinal fusion? The case for spinal fusion is unproved. BMJ (Clinical research ed.), 1996; 312(7022):39-40.
O’Beirne J, O’Neill D, Gallagher J, Williams D. Spinal fusion for back pain: a clinical and radiological review. Journal of Spinal Disorders, 1992; 5(1):32-38.

Authors
Dr Simon Petrides MB BS DM-SMed DO Dip Sports Med FFSEM (UK & I)
Dr John Tanner BSc MB BS FFSEM D M-S M DSMSA
Dr. Keith Bush MB BS MD (Lond) FFSEM(UK)