25th April 2023, Dr Chee L Khoo
We may not have many patients with neuropathic pain but patients with neuropathic pain can be heartsinks. Most of the time, nothing seems to work. It can be quite frustrating when anti-depressants after anti-depressants don’t work. The old tricyclics often don’t work either. What about pregabalin? Nope. What about gabapentin? Nope. What about long-acting opioids or tramadol? Well, opioid seems to be a dirty word these days especially amongst our younger graduates. It doesn’t help much any way. Neither does the tramadol. What about combinations of the above agents? Which combinations or permutations have a better chance of working? Can we mix them?
Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory system” (1). It has a prevalence of 7% to 10% (2). It is often said that these patients need a multidisciplinary, multimodal approach to neuropathic pain management but the so-called multi-disciplinary pain clinic don’t necessarily have any better success that we have in primary care. We know our patients better. At the end of the day, pharmacotherapy is an important treatment modality. Based on available evidence, currently recommended neuropathic pain pharmacotherapy includes tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors (SNRIs), pregabalin, and gabapentin as a first-line therapy. The second-line therapy include lidocaine patches, capsaicin high-concentration patches, and tramadol (3).
Naturally, agents would have been approved because they are shown to be efficacious in clinical trials. At most, they reduce pain by 25-40% at the most and almost always as monotherapy. Further, they only work in 40-60% patients at the most. There is further frustration as many of these agents comes with adverse events which limit the maximal dose patients can be prescribed. Most of the time, additional agents are introduced to assist in the symptom management. However, the evidence behind combination therapy is very limited. Yet, we do it despite the lack of evidence.
Back in 2012, there was a Cochrane Collaboration systematic review looking at various drug combinations. However, the limited number of available studies for any one specific combination preclude the recommendation of any one specific drug combination for neuropathic pain. That wasn’t very helpful. Since then, there has been more studies and a recent meta-analysis was conducted and was published in Pain two months ago (4).
As per usual, MEDLINE and EMBASSE were searched for randomised controlled trials published between Jan 2012 and June 2020. The primary efficacy outcomes were measured using validated methods of participant-reported pain intensity and relief and included any of the following: proportion of participants reporting >30% pain reduction from baseline, moderate pain relief, and moderate global improvement. New meta-analyses were conducted to compare combination efficacy with monotherapy wherever 2 or more similar studies were available.
After screening 2566 studies and excluding duplicates and unsuitable studies, 19 new studies (N=2776) we included in the meta-analysis. The studies evaluated the combination of an opioid with a gabapentinoid (with tapentadol being classified as an opioid); 4 studies evaluated the combination of an opioid with an antidepressant; 3 studies evaluated the combination of a gabapentinoid with an antidepressant; 5 studies evaluated the combination of ketamine with an agent from a different drug class; 7 studies involved a combination with topical analgesics and 15 studies evaluated various other analgesic combinations. Neuropathic pain conditions studied were:
- peripheral neuropathic pain (diabetic neuropathy and postherpetic neuralgia)
- low back pain with a neuropathic component
- HIV-associated polyneuropathy
- lumbar radiculopathy
- neuropathic cancer pain
- chemotherapy-induced peripheral neuropathic pain,
- Diabetic neuropathy,
- Postherpetic neuralgia
- chronic/refractory neuropathic pain of mixed etiology
- multiple sclerosis
- lumbar spinal stenosis,
- radiation-induced plexopathy
- Charcot–Marie–Tooth disease type 1
- chronic phantom limb pain and
- spinal cord injury–related chronic neuropathic pain
So, what did they find? The combination therapies was categorised into:
Opioids with gabapentinoid (including pregabalin)
There were 6 studies in the meta-analysis. 3 studies evaluated the combination of gabapentin with an opioid; one with morphine , one with oxycodone and one with any opioid. 3 studies evaluated the combination of pregabalin with an opioid: one with morphine, one with tapentadol (classified here as an opioid), and one with oxycodone.
3 studies failed to demonstrate a difference between opioid–gabapentinoid combination and opioid monotherapy (including tapentadol) in providing at least moderate/good pain relief/>30% pain reduction. 2 studies did demonstrate a difference between opioid–gabapentinoid combination and gabapentin monotherapy in providing at least moderate/good relief/>30% pain reduction (RR 1.27).
Significant adverse events were noted with opioid–gabapentinoid combination treatment, exhibiting higher rates of constipation, dry mouth, nausea, dizziness, fatigue, and somnolence, compared with monotherapy groups. In one study, pregabalin–morphine therapy was associated with less constipation compared with morphine monotherapy.
There were 2 studies which were not included in the meta-analysis but the mean minimal effective dose of morphine was significantly lower with pregabalin–morphine combination vs the placebo control period and baseline, also noting a significant difference in MED between placebo control and baseline.
Opiods with anti-depressants
4 studies evaluated the combination of opioid and anti-depressants. Two studies evaluated the combination of nortriptyline and sustained-release morphine,30,44 one evaluated the combination of duloxetine and methadone,37 and one evaluated the combination of amitriptyline and morphine.
1 study failed to demonstrate a difference between opioid-antidepressant combinations and opioid monotherapy in providing at least moderate/good pain relief/>30% pain reduction. 1 study did demonstrate a difference between opioid–antidepressant combinations and antidepressant monotherapy. In two studies were not included in meta-analyses, there were no significant differences found between the treatment groups in mean 24-hour pain intensity, global pain relief, and opioid requirement.
Gabapentinoids with anti-depressants
3 studies were reviewed – imipramine with pregabalin, nortriptyline with gabapentin and duloxetine with pregabalin. Meta-analysis of 2 or 3 studies failed to demonstrate a difference between gabapentinoid–antidepressant combination and gabapentinoid monotherapy but a meta-analysis of 3 studies did demonstrate a difference between gabapentinoid–antidepressant combination and antidepressant monotherapy.
Other combinations
There were a number of studies using i.v. ketamine plus another agent – ketamine + magnesium sulphate, ketamine + gabapentin, ketamine + calcitonin, ketamine + methadone, ketamine + amitriptyline and ketamine + carbamazepine. Only the ketamine + gabapentin and ketamine + calcitonin showed benefit over the monotherapy arms.
There were also studies comparing various agents with and without topical agents. Four studies evaluated the combination of amitriptyline with ketamine – 3 studies combined them in a cream and one study evaluated a compound gel also including baclofen and amitriptyline HCl. One study combined doxepin, with capsaicin in a cream; Another study combined a glyceryl trinitrate spray with sodium valproate; and yet another combined tocopheryl phosphate with oxycodone in a patch.
Only the glyceryl trinitrate spray (with sodium valproate) and the compound gel (with baclofen and amitriptyline) reported reduction in pain intensity.
There were further innovative combination therapies – pregabalin with limaprost ( a prostaglandin E1 analogue), duloxetine + Opioid + pregabalin, pregabalin + NSAID, gabapentin + nabilone (a cannabinoid), gabapentin + alpha lipoic acid and pregabalin + duloxetine + Epalrestat ( an aldose reductase inhibitor). The combinations containing gabapentin or pregabalin with another agent reported a reduction in pain intensity. Pregabalin–epalrestat was reported to be superior to duloxetine–epalrestat in treating diabetic neuropathy but potential statistical significance was unclear.
Many combination trials reported that drug doses were lower during combination therapy compared with monotherapy likely due to the additive effects of sedative and other CNS depressant effects of the combined drugs thus precluding further dose increases.
In summary, as you can see, the efficacy of combination therapies is unpredictable. It would seem that overall, the combination of opioid-gabapentinoid, opioid-antidepressant and gabapentinoid-anti-depressant have not shown to be better than monotherapy. However, many of trials were of short duration and involve small samples. There were no one treatment combination that stands out to be highly effective over others. The authors concluded that “just because evidence from 40 trials of combinations did not demonstrate superiority over monotherapy does not necessarily mean that other drug combinations or some of these studied combinations in different clinical settings do not produce favourable results. Thus, further research is needed, including trials of other drug combinations—possibly those involving nonsedating agents—to identify clinical settings and specific combinations that safely provide added benefit.”
So, if you are struggling to find the “right” combination of agents for your patient with neuropathic pain, you are not alone.
References:
- Jensen TS, Baron R, Haanpa¨ a¨ M, Kalso E, Loeser JD, Rice ASC, Treede R-D. A new definition of neuropathic pain. PAIN 2011;152:2204–5.
- van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. PAIN 2014;155:654–62.
- Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpa¨ a¨ M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice ASC, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73.
- Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Jul 11;2012(7):CD008943. doi: 10.1002/14651858.CD008943.pub2.
- Balanaser M, Carley M, Baron R, Finnerup NB, Moore RA, Rowbotham MC, Chaparro LE, Gilron I. Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis. Pain. 2023 Feb 1;164(2):230-251. doi: 10.1097/j.pain.0000000000002688.