Who really benefits from drug combinations and long titrations for pain? - Authors' reply.

Findings from Solomon Tesfaye and colleagues’ OPTION-DM trial1Tesfaye S Sloan G Petrie J et al.Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.Lancet. 2022; 400: 680-690Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar are a useful but intellectually challenging contribution to understanding drug treatment of painful neuropathy. It reiterates a popular expert opinion that gabapentin must be given three times daily and “requires a long titration period of up to 2 months to avoid toxicity”.1Tesfaye S Sloan G Petrie J et al.Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.Lancet. 2022; 400: 680-690Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar Gabapentin and pregabalin have similar elimination half-lives, via renal excretion. Twice daily administration gave pregabalin a marketing advantage when the patent on gabapentin expired. As for most other symptomatic drug therapies, evidence for dose response from analgesics is tenuous; effects are maximal within days to a few weeks, and prolonged titration is therefore pointless or harmful.2Moore RA Cai N Skljarevski V Tolle TR Duloxetine use in chronic painful conditions—individual patient data responder analysis.Eur J Pain. 2014; 18: 67-75Crossref PubMed Scopus (120) Google Scholar, 3Therapeutics Initiative[134] Finding the lowest effective dose for non-opioid analgesics.https://www.ti.ubc.ca/2022/02/27/134-finding-the-lowest-effective-dose-for-non-opioid-analgesics/Date accessed: December 20, 2022Google Scholar Early analgesia has been reported previously in pioneering trials using morphine, gabapentin, and nortriptyline.4Gilron I Bailey JM Tu D et al.Morphine, gabapentin, or their combination for neuropathic pain.N Engl J Med. 2005; 352: 1324-1334Crossref PubMed Scopus (966) Google Scholar, 5Gilron I Bailey JM Tu D Holden RR Jackson AC Houlden RL Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.Lancet. 2009; 374: 1252-1261Summary Full Text Full Text PDF PubMed Scopus (387) Google Scholar Close inspection of figure 2 of the Article1Tesfaye S Sloan G Petrie J et al.Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.Lancet. 2022; 400: 680-690Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar shows that most of the decline in mean pain score occurs within the 2-week monotherapy titration phase. The final titration step, followed by the addition of a second drug after 6 weeks of monotherapy, accomplishes little more. Patients’ global impression was recorded only at the end of each two-drug pathway, not during monotherapy. Excluding patients with ischaemic heart disease and heart failure, dysrhythmias, or prostatic hyperplasia limits generalisability of this study to older people. Treatment-related serious adverse events cannot be assessed reliably among only 130 people treated for less than 1 year. Rather than being evidence for prescribers to titrate to the maximum tolerated dose or encourage polypharmacy, I interpret this important trial as yet another reason for caution about dose titration and combination drug therapies alike. I declare no competing interests. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trialTo our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. Full-Text PDF Open Access