Efficacy and/or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol as Treatment for Musculoskeletal Pain

Transcription

1 Evidence-Based Practice Group Answers to Clinical Questions Efficacy and/or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol as Treatment for Musculoskeletal Pain A Rapid Systematic Review By WorkSafeBC Evidence-Based Practice Group Dr. Craig Martin Manager, Clinical Services Chair, Evidence-Based Practice Group March 2017 Clinical Services Worker and Employer Services

2 Musculoskeletal Pain i About this report Efficacy and/or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol as Treatment for Musculoskeletal Pain Published: March 2017 About the Evidence-Based Practice Group The Evidence-Based Practice Group was established to address the many medical and policy issues that WorkSafeBC officers deal with on a regular basis. Members apply established techniques of critical appraisal and evidence-based review of topics solicited from both WorkSafeBC staff and other interested parties such as surgeons, medical specialists, and rehabilitation providers. Suggested Citation WorkSafeBC Evidence-Based Practice Group, Martin CW. Efficacy and/or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol as Treatment for Musculoskeletal Pain. Richmond, BC: WorksafeBC Evidence-Based Practice Group; March Contact Information Evidence-Based Practice Group WorkSafeBC PO Box 5350 Stn Terminal Vancouver BC V6B 5L5 craig.martin@worksafebc.com Phone Toll-free ext 7417

3 Musculoskeletal Pain 1 Objective To determine whether there is any evidence to support the efficacy and/or effectiveness of a compound comprising of 5% gabapentin, 5% ketamine, 2.5 g lidocaine and 2.5 g tramadol in treating musculoskeletal pain, especially for muscle sprain/strain and contusion? Methods A comprehensive literature search was conducted on March 29, The search was done on commercial medical literature databases, including the Cochrane Database of Systematic Reviews (2005 to March 22, 2017), ACP Journal Club (1991 to March 2017), Database of Abstracts of Reviews of Effects (1st Quarter 2016), Cochrane Central Register of Controlled Trials (February 2017), UK NHS Health Technology Assessment (4th Quarter 2016), UK NHS Economic Evaluation Database (1st Quarter 2016), BIOSIS Previews (1969 to 2008), Embase (1974 to 2017 March 28), MEDLINE Epub Ahead of Print, Medline In-Process & Other Non-Indexed Citations, MEDLINE Daily Update and MEDLINE (1946 to Present), that are available through Ovid platform. The searches were conducted by employing combinations of keywords, consisting of: 1. (((gabapentin 5%) OR (gabapentin 2.5 g)) AND ((ketamine 5%) OR (ketamine 2.5 g)) AND (lidocaine 2.5 g) AND (tramadol 2.5 g)) No published studies were identified from this search. 2. (gabapentin AND ketamine AND lidocaine AND tramadol) AND (topical OR compound) Twenty-four (1-24) published studies were identified through this search. One (17) study out of the 24 identified was thought to be relevant and was retrieved in full for further appraisal. However, this article did not provide any data/information on the efficacy/effectiveness of topical or compound analgesics in general, or gabapentinketamine-lidocaine-tramadol compound in particular. 3. (topical tramadol)

4 Musculoskeletal Pain 2 The keywords topical tramadol were specifically searched since there was a concern with the fact that an opioid is part of this particular compound Seven (25-31) published studies were identified through this search. Five (25,27,29-31) published studies were identified from the above seven studies as investigating the efficacy/effectiveness of topical tramadol. However, upon examination of the titles and abstracts of these five (25,27,29-31) studies, none of these studies were relevant to the objective of this systematic review as all five studies were conducted among children, to treat acute post-operative pain of post-tonsillectomy or tooth extraction. No limitations, such as on the language or date of publication, were employed in this search. Published studies in the possession of the Evidence-Based Practice Group from previous systematic reviews on topical analgesics, as well as resulting from the Group s daily literature surveillance were also searched. Six (32-37) further studies were retrieved from this collection and presented below. Manual searches were also conducted on the references of the fully retrieved articles. No further study was identified through this search. Results This systematic review failed to identify any published study investigating the efficacy/effectiveness of a gabapentin, ketamine, lidocaine and tramadol compound, in any concentration/composition. In the last five years, the United States has seen a nearly five-fold increase in the number of compounded drugs available via prescription (32). Such topical compounds are advertised as featuring numerous beneficial effects, including: o The notion that with topical drugs, patients will theoretically avoid systemic absorption and may thus also avoid subsequent side effects o The combining of multiple agents into a single preparation reduces the number of tablets or capsules needed and thus reduces the difficulty experienced by patients who have trouble swallowing oral preparations o The process of compounding drugs can omit ingredients that cause allergic or other adverse reaction(s) in the patient However, in general, evidence on the efficacy/effectiveness, either pertaining to each individual compound ingredient or pertaining to the

5 Musculoskeletal Pain 3 compounds itself, are lacking (32) ; additionally, quality control regarding the process of compounding are questionable and potential adverse events cannot be discounted (36,37). Compound drugs are not US FDA or Health Canada approved; as such quality and safety standards in the manufacturing of this compound can be an issue. The Ohio State Board of Pharmacy minutes reveal that when quality tests were performed on some compounded products, the potency of the tested drugs reflected a sizeable difference (ranging from approximately 27% to 85%) from the stated/listed amounts of active ingredients as found on the products labels. Also in Ohio, the testing for sterility, fungi, or endotoxins conducted on some compound samples (prior to dispensing to customers) showed fungal contamination likely were present in the compound drugs already dispensed/distributed to patients. To date, the transdermal absorption of drugs and its subsequent deep tissue delivery, a complex process with many factors potentially influencing the penetration mechanism, is not yet fully understood (34-36). As such, evidence on the efficacy/effectiveness of such topical compound medication is urgently needed prior to its application. o The stratum corneum of the skin is considered to be the greatest barrier to drug absorption, and the science of dermal absorption, penetration, and distribution remains an area of study under further development. o Drug absorption into and through the skin into muscle depends on the physical and chemical characteristics of the drug. These include molecular size, lipophilicity, permeability, and fraction unbound in viable skin. Additionally, the concentration of the drug, duration of contact, and use of an occlusive barrier over a topical agent can all alter drug absorption and penetration. o Once a drug is absorbed into the skin, transdermal penetration into underlying tissue is needed for joint or muscle pain to be relieved. It is believed that the most important factor for flux and drug distribution is the molecular size of the drug. Other important drug characteristics are: o A more lipid soluble drug is expected to have a greater depth of penetration o A higher fraction of un-ionized drug (permeability) may also play a role in absorption. The ph of the vehicle has a strong influence on drug ionization o A higher unbound fraction of drug is also correlated with drug clearance from viable skin to the muscle o Another important component of topical drug efficacy is the vehicle. The composition of the vehicle (cream, gel or ointment), ph, lipid

6 Musculoskeletal Pain 4 characteristics and drug solubility in the vehicle, all influence the amount and depth of absorption of a drug into the skin and underlying tissues. Summary/Conclusions At present, there is no evidence regarding the efficacy/effectiveness, or potential side effects, of compounds consisting of gabapentin, ketamine, lidocaine and tramadol, of any concentration, in treating pain. At present, there is some evidence regarding the efficacy/effectiveness of topical tramadol in treating short term acute pain in children. At present, the science on topical drug delivery still requires further development, which may affect the current efficacy/effectiveness and safety of the drugs involved. References 1. Anonymous. Background. Paediatric. Anaesthesia. 22 (SUPPL. 1) (pp 1-79), Date of Publication: July Baron, R. Neuropathic pain: A clinical perspective. Handbook. of Experimental Pharmacology. 194 (pp 3-30), Date of Publication: Beecham Emma; Candy Bridget; Howard Richard; McCulloch Renee; Laddie, J. o.; Rees Henrietta; Vickerstaff Victoria; BluebondLangner Myra, and Jones Louise. Pharmacological interventions for pain in children and adolescents with life-limiting conditions. Cochrane. 2016; (4). 4. Centre for Reviews and Dissemination. A systematic review of pharmacologic treatments of pain after spinal cord injury. Database. 2015; (2). 5. De Leon-Casasola, O. New developments in the treatment algorithm for peripheral neuropathic pain. Pain. Medicine. 12 (SUPPL. 3) (pp S100-S108), Date of Publication: July Fallon M.T.; Colvin, L., and Rowbotham D.J. Neuropathic pain in cancer. British. Journal of Anaesthesia. 111 (1) (pp ), Date of Publication: July Gilron, I. and Coderre T.J. Emerging drugs in neuropathic pain. Expert. Opinion on Emerging Drugs. 12 (1) (pp ), Date of Publication: March Gilron, I.; Jensen T.S., and Dickenson A.H. Combination pharmacotherapy for management of chronic pain: From bench to bedside. The. Lancet Neurology. 12 (11) (pp ), Date of Publication: November Gilron, I.; Watson C.P.N.; Cahill C.M., and Moulin D.E. Neuropathic pain: A practical guide for the clinician. CMAJ. 175 (3) (pp ), Date of Publication: 01 Aug Hagen E.M. and Rekand, T. Management of Neuropathic Pain Associated with Spinal Cord Injury. Pain. and Therapy. 4 (1) (pp 51-65), Date of Publication: 22 Jun Hempenstall, K.; Nurmikko T.J.; Johnson R.W.; A'Hern R.P., and Rice A.S.C. Analgesic

7 Musculoskeletal Pain 5 therapy in postherpetic neuralgia: A quantitative systematic review. PLoS. Medicine. 2 (7) (pp ), Date of Publication: Hocking, G. and Cousins, M. Postherpetic neuralgia an update on management. Medicine. Today. 3 (11) (pp 16-26), Date of Publication: 01 Nov Johnson R.W. and Whitton T.L. Management of herpes zoster (shingles) and postherpetic neuralgia. Expert. Opinion on Pharmacotherapy. 5 (3) (pp ), Date of Publication: March Judkins, D. and Goree, J. Multimodal approach to the treatment of CRPS. Regional. Anesthesia and Pain Medicine. Conference: 14th Annual Pain Medicine Meeting of the American Society of Regional Anesthesia and Pain Medicine, ASRA Miami, FL United States. Conference Start: Conference End: Conference Publication: (var.pagings). 41 (2) (no pagination), Date of Publication: March-April Kanazi G.E.; Johnson R.W., and Dworkin R.H. Treatment of postherpetic neuralgia: An update. Drugs. 59 (5) (pp ), Date of Publication: Kern K.-U. and Weiser, T. Topical ambroxol for the treatment of neuropathic pain: An initial clinical observation. English version. Schmerz. 29 (pp 89-96), Date of Publication: 01 Dec Mao, J.; Gold M.S., and Backonja, M. Combination drug therapy for chronic pain: A call for more clinical studies. Journal. of Pain. 12 (2) (pp ), Date of Publication: February Martinez, V. and Lanteri-Minet, M. Current pharmacological treatment, guidelines and prospects. [French]. Douleur. et Analgesie. 23 (2) (pp 93-98), Date of Publication: June Murphy E.J. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesthesia. and Intensive Care. 33 (3) (pp ), Date of Publication: June Napenas J.J. and Zakrzewska J.M. Diagnosis and management of trigeminal neuropathic pains. Pain. Management. 1 (4) (pp ), Date of Publication: July Niv, D. and Maltsman-Tseikhin, A. Postherpetic neuralgia: The never-ending challenge. Pain. Practice. 5 (4) (pp ), Date of Publication: December Paster, Z. and Morris C.M. Treatment of the localized pain of postherpetic neuralgia. Postgraduate. Medicine. 122 (1) (pp ), Date of Publication: January Scheinfeld, N. Topical treatments of skin pain: A general review with a focus on hidradenitis suppurativa with topical agents. Dermatology. Online Journal. 20 (7) (no pagination), Date of Publication: Vranken J.H. Elucidation of pathophysiology and treatment of neuropathic pain. Central. Nervous System Agents in Medicinal Chemistry. 12 (4) (pp ), Date of Publication: Akbay, B. K.; Yildizbas, S.; Guclu, E.; Yilmaz, S.; Iskender, A., and Ozturk, O. Analgesic efficacy of topical tramadol in the control of postoperative pain in children after tonsillectomy. Journal. of Anesthesia. 24(5):705-8, 2010 Oct. 26. Cuvas Apan, O.; Ozer, M. A.; Takir, S.; Apan, A., and Sengul, D. Effect of topical administration of tramadol on corneal wound healing in rats. International. Ophthalmology. 36(5):675-80, 2016 Oct.

8 Musculoskeletal Pain Gonul, O.; Satilmis, T.; Ciftci, A.; Sipahi, A.; Garip, H., and Goker, K. Comparison of the Effects of Topical Ketamine and Tramadol on Postoperative Pain After Mandibular Molar Extraction. Journal. of Oral & Maxillofacial Surgery. 73(11):2103-7, 2015 Nov. 28. Kayacan, N.; Karsli, B.; Ozbilim, G.; Bigat, Z.; Erman, M., and Karpuzoglu, G. Intravesical analgesia for ambulatory urologic procedures: A histopathological study. Ambulatory. Surgery. 10 (4) (pp ), Date of Publication: May Malik, S.; Wadhwani, J.; Zafar, S., and Aftab, S. Analgesic efficacy of topical tramadol in the control of postoperative pain in children after tonsillectomy. Anaesthesia. Pain and Intensive Care. Conference: 11th International Anaesthesia, Pain and Intensive Care Conference, APICON 11. Bhurban Pakistan. Conference Start: Conference End: Conference Publication: (var.pagings). 15 (2) (pp 158), Date of Publication: July-September Malik, S. Wadhwani J, Zafar S, Aftab S. Analgesic efficacy of topical tramadol in the control of postoperative pain in children after tonsillectomy. Anaesthesia. Pain and Intensive Care. Vol.15 (2), pp.158, Tekelioglu, U. Y.; Apuhan, T.; Akkaya, A.; Demirhan, A.; Yildiz, I.; Simsek, T.; Gok, U., and Kocoglu, H. Comparison of topical tramadol and ketamine in pain treatment after tonsillectomy. Paediatric. Anaesthesia. 23(6): , 2013 Jun. 32. Walls AP, Johjson S, Nguyen M et al. (2014). Compounding is Confounding Workers Compensation. Downloaded from in March Sommer C, Cruccu G, Topical Treatment of Peripheral Neuropathic Pain: Applying the Evidence, Journal of Pain and Symptom Management (2017), doi: /j.jpainsymman Lee CM and Maibach HI. Deep Percutaneous Penetration into Muscles and Joints. J Pharm Sci 2006;95: Jepps OG, Dancik Y, Anissimov YG and Roberts MS. Modeling the human skin barrier - Towards a better understanding of dermal absorption. Advanced Drug Delivery Reviews 2013;65: Higaki K, Asai M, Suyama T et al. Estimation of intradermal disposition kinetics of drugs: II. Factors determining penetration of drugs from viable skin to muscular layer. International Journal of Pharmaceutics. Green DM, Jones AC and Brain KR. Content variability of active drug substance in compounded oral 3,4-diaminopyridine products. Journal of Clinical Pharmacy and Therapeutics. 2012;37: Sasich LD and Sukkari SR. Unknown Risks of Pharmacy-Compounded Drugs. The Journal of the American Osteopathic Association. February 2008;108(2):86.

9 Musculoskeletal Pain 7 Appendix 1 WorkSafeBC - Evidence-Based Practice Group Levels of Evidence (adapted from 1,2,3,4) Evidence from at least 1 properly randomized controlled trial (RCT) or systematic review of RCTs. Evidence from well-designed controlled trials without randomization or systematic reviews of observational studies. Evidence from well-designed cohort or case-control analytic studies, preferably from more than 1 centre or research group. Evidence from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees. References 1. Canadian Task Force on the Periodic Health Examination: The periodic health examination. CMAJ. 1979;121: Houston TP, Elster AB, Davis RM et al. The US Preventive Services Task Force Guide to Clinical Preventive Services, Second Edition. AMA Council on Scientific Affairs. American Journal of Preventive Medicine. May 1998;14(4): Scottish Intercollegiate Guidelines Network (2001). SIGN 50: a guideline developers' handbook. SIGN. Edinburgh. 4. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ. Aug 5, 2003;169(3):