Devin Reed, MD
Resident
University of Mississippi Medical Center
Jackson, Mississippi
Clayton Newell, MD
Interventional Pain Management Fellow
University of Mississippi Medical Center
Jackson, Mississippi
Anesh Rugnath, MD
Interventional Pain Management Attending
University of Mississippi Medical Center
Jackson, Mississippi
The World Health Organization (WHO) reports that the leading cause of disability is pain, which has been the case since 1990. Chronic pain is often multifactorial, with the International Association for Study of Pain (IASP) accounting for neuropathic pain to affect as many as 1 in 30 across the adult population, with some demographics having a higher incidence. Given such high incidence and overall public health costs, the analytic study of efficacious treatment is pertinent in neuropathic pain.
Tramadol is a centrally acting synthetic opioid analgesic. It is available as a racemic mixture, metabolizing by demethylation to an active metabolite. The (+) enantiomer has a low affinity to mu receptors and inhibits serotonin reuptake, while the (-) enantiomer inhibits norepinephrine reuptake. Despite fitting into Step 2 of the WHO analgesic ladder and being listed as a second-tier treatment option for neuropathic pain by multiple international pain societies: IASP, Canadian Pain Society, NICE (UK National Institute for Health Care Excellence), and EFNS (European Federation of Neurological Societies), the most recent Cochran study in 2017 found low to very low quality of evidence to support the use of tramadol in the treatment of neuropathic pain.
This literary review aims to delve into the most current evidence to assess the analgesic efficacy of tramadol for chronic neuropathic pain in adults to understand the best practice better.
Methods:
The World Health Organization (WHO) reports that the leading cause of disability is pain, which has been the case since 1990. Chronic pain is often multifactorial, with the International Association for Study of Pain (IASP) accounting for neuropathic pain to affect as many as 1 in 30 across the adult population, with some demographics having a higher incidence. Given such high incidence and overall public health costs, the analytic study of efficacious treatment is pertinent in neuropathic pain.
Tramadol is a centrally acting synthetic opioid analgesic. It is available as a racemic mixture, metabolizing by demethylation to an active metabolite. The (+) enantiomer has a low affinity to mu receptors and inhibits serotonin reuptake, while the (-) enantiomer inhibits norepinephrine reuptake. Despite fitting into Step 2 of the WHO analgesic ladder and being listed as a second-tier treatment option for neuropathic pain by multiple international pain societies: IASP, Canadian Pain Society, NICE (UK National Institute for Health Care Excellence), and EFNS (European Federation of Neurological Societies), the most recent Cochran study in 2017 found low to very low quality of evidence to support the use of tramadol in the treatment of neuropathic pain.
This literary review aims to delve into the most current evidence to assess the analgesic efficacy of tramadol for chronic neuropathic pain in adults to understand the best practice better.
Results:
Three systematic reviews comprising 26 randomized trials and meta-analyses were identified, evaluating the utilization of tramadol of 100mg daily and increased to as much as 400mg daily over at least 4-6 weeks of treatment. Across studies, patients had experienced neuropathic pain symptoms for at least three months. Patient populations were an approximately equal mix of gender.
Not all studies reported measurable pain reduction outcomes, with some focusing on patient satisfaction, safety margins, and adverse drug reactions of tramadol therapy for chronic neuropathic pain.
A reduction of pain intensity by at least fifty percent was elucidated in 7 of 16 studies with tramadol therapy. Tramadol was consistently shown to provide more significant relief than placebo but not always of statistical significance. Tramadol was not shown to have a more significant pain intensity reduction than other active therapies, such as NSAIDs or duloxetine, but not less pain relief either statistical significance.
Treatment with tramadol resulted in higher adverse events than placebo in those studies reporting adversity; however, none were deemed critical, and no deaths resultant. No statistical significance between adverse outcomes of tramadol to other opioids or non-narcotic treatments was observed in the two studies.
Conclusion:
A fair body of information has developed to evaluate the use of tramadol in neuropathic pain. However, most of these are small single-center studies. Heterogeneity among the study population, differing outcome measures, lack of transparency of pain reduction scores, and a variety of therapeutic intervention arms make random-effect analysis challenging as one takes the body of evidence into greater perspective. Risks for potential bias may magnify the apparent benefits of tramadol.
However, tramadol consistently outperforms placebo in pain reduction >50% and patient satisfaction through 6-12wks of therapy. This research suggests tramadol has consistent therapeutic efficacy in neuropathic pain. Tramadol also provides pain reduction similar to other modal agents in chronic neuropathic pain relief.
Given the potential for adverse symptomology and the low risk of addiction with tramadol therapy, evidence suggests similar therapeutic pain relief can be achieved with other modal agents. This research aligns with many international criteria, despite the most recent Cochrane study in which tramadol doses were used for refractory pain rescue therapy in shorter courses.
There is still ample room for further study of tramadol's effect on neuropathic pain relief. Larger population studies with tramadol versus tramadol + Tier 1 therapy (such as gabapentin or duloxetine) may help illuminate any multi-modal effects or additive or supra-additive benefits while minimizing bias and other confounding factors. Such data could help further support practicing guidelines on an international basis, as well as help, optimize patients' neuropathic pain relief.
References: Barakat, A. Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs 33, 481–501 (2019).
Cruccu, G., Truini, A. A review of Neuropathic Pain: From Guidelines to Clinical Practice. Pain Ther 6, 35–42 (2017).
Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD003726.
Jung SY, Jang EJ, Nam SW, et al. Comparative effectiveness of oral pharmacologic interventions for knee osteoarthritis: a network meta-analysis. Mod Rheumatol. 2018: 1–8.
Stella Chen and Charlene Argáez. Tramadol for the Management of Pain in Adult Patients: A Review of Clinical Effectiveness - An Update. CADTH Rapid Response Report: Summary with Critical Appraisal. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018.
Vos T, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388(10053):1545.