Efficacy And/Or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol As Treatment for Musculoskeletal Pain”

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

WorkSafeBC Evidence-Based Practice Group

Dr. Craig Martin Manager, Clinical Services Chair, Evidence-Based Practice Group

March 2017

Clinical Services – Worker and Employer Services Efficacy and/or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol as Treatment for 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 2017.

Contact Information Evidence-Based Practice Group WorkSafeBC PO Box 5350 Stn Terminal Vancouver BC V6B 5L5

Email  [email protected] Phone  604 279-7417 Toll-free  1 888 967-5377 ext 7417

WorkSafeBC Evidence-Based Practice Group March 2017 www.worksafebc.com/evidence Efficacy and/or Effectiveness of Compound of Gabapentin, Ketamine, Lidocaine and Tramadol as Treatment for 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, 2017. • 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 gabapentin- ketamine-lidocaine-tramadol compound in particular.

3. (topical tramadol)

. 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

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

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

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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 1 (RCT) or systematic review of RCTs. Evidence from well-designed controlled trials without 2 randomization or systematic reviews of observational studies. Evidence from well-designed cohort or case-control analytic 3 studies, preferably from more than 1 centre or research group. Evidence from comparisons between times or places with or 4 without the intervention. Dramatic results in uncontrolled

Opinions of respected authorities, based on clinical experience, 5 descriptive studies or reports of expert committees.

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3. 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):207- 208.

WorkSafeBC Evidence-Based Practice Group March 2017 www.worksafebc.com/evidence