Therapeutics Letter 134 explores effective dosing for non-opioid analgesics. Conclusions: Most patients do not obtain clinically meaningful pain relief at any dose of cyclobenzaprine, duloxetine, gabapentin, or pregabalin. High doses are unlikely to improve analgesia more than lower doses. They do increase harms. Clinical impacts of dose changes (good or bad) should usually be apparent within 1 week. Spontaneous improvement can appear to be a beneficial drug effect, even when it would have occurred without drug therapy. Try short therapeutic trials and periodic reassessment of patients whose pain improves during drug therapy.
Keywords:
Analgesia; Analgesics, Non-Narcotic; Cyclobenzaprine; Duloxetine Hydrochloride; Gabapentin; Pain; PregabalinSome prescribers “titrate” patients to high “target” doses of cyclobenzaprine, duloxetine, gabapentin or pregabalin; and some guidelines advocate progressive dose increases.
1–3 Whether intended to minimize adverse effects, or to improve pain relief, this approach is not supported by evidence from randomized clinical trials (RCTs). A prolonged “titration strategy” can increase costs, and higher doses can be expected to increase adverse effects; but do patients achieve better analgesia in return?
Evidence is consistent that a minority of patients achieves clinically meaningful pain relief from any dose of cyclobenzaprine (at best 1 in 4), duloxetine (at best 1 in 6), or gabapentin/pregabalin (at best 1 in 6).4–8 Generally, patients can tell within a week whether pain relief is sufficient to warrant any adverse effects they experience. Thus, prolonged therapeutic trials are pointless, and may be expensive or harmful. Conversely, brief therapeutic trials and periodic reassessment can help prescribers distinguish beneficial drug effects from spontaneous improvement of pain over time. A linked video (www.ti.ubc.ca/letter134) records one woman’s adverse experience of a prolonged dose-escalation strategy with gabapentin.
Other groups have reached similar or more conservative conclusions. For gabapentin, pregabalin, and duloxetine, a 2021 Canadian systematic review reported numbers needed to treat (NNT) of 6–7 for a “clinically meaningful benefit” defined as a ≥30% reduction in pain or pain and function.9 Pain researchers at Oxford University apply a more stringent definition of “response” that requires a ≥50% improvement in pain score from baseline. They conclude that “no single drug will treat successfully more than a minority of patients with a painful condition. Success or failure can be determined within 2–4 weeks.” 10
Dose increases usually do not improve benefits
RCTs showed that cyclobenzaprine doses <10mg/d are preferable to higher doses.4 For duloxetine, gabapentin and pregabalin, we evaluated RCTs included in 4 Cochrane systematic reviews for chronic neuropathic pain or fibromyalgia).5–8 These trials show that exceeding what we can term “evidence-informed ceiling doses” does not reduce mean pain scores. Older people warrant extra caution. Reductions in kidney function reduce excretion of gabapentin, pregabalin, and duloxetine and increase vulnerability to anticholinergic effects (cyclobenzaprine, duloxetine), postural hypotension (cyclobenzaprine) and to sedative and balance effects of all four drugs.
How soon are drug effects detectable?
Cyclobenzaprine effects on painful back spasm are detectable on day 1 or 2 of treatment.11 Effects are minimal and cyclobenzaprine does not reduce disability.12,13 Duloxetine effects on neuropathic pain and fibromyalgia separate maximally from placebo by 2 weeks, and by 4–5 weeks for osteoarthritis and low back pain, although the NNTs for a ≥50% “response” are all about 6–10.14 Gabapentin and pregabalin RCTs typically assessed patients first at 1–2 weeks, but short drug half-lives predict effects within 1 day at any dose. An experiment with gabapentin 900mg single dose for acute shingles pain showed clear separation from placebo at 1–2 hours.15 In clinical practice, it is rational to reassess people within 1 week of starting a trial of therapy.
Harms are dose-dependent
Individual RCTs, Cochrane reviews, and product monographs all show dose-dependent increases in harms. Somnolence, dizziness, and nausea are common with all four drugs.
Cyclobenzaprine and duloxetine frequently cause anticholinergic effects. These include dry mouth, accelerated tooth decay, and difficulty swallowing due to reduced salivation; delayed stomach emptying and constipation due to reduced gut motility; difficulty urinating or urinary retention; impairment of visual accommodation; and cognitive impairment. During extreme heat events, decreased sweating may become an increasingly important clinical problem. Like other tricyclics, cyclobenzaprine blocks alpha receptors and can cause postural hypotension, reported by patients as “light-headedness”, “dizziness,” or falls.
Gabapentin and pregabalin not only have prominent CNS effects, but also cause edema that may be confused with heart failure or kidney disease. Evidence for increased abuse potential of gabapentin and pregabalin due to their euphoric and dissociative effects (especially in combination with opioids and for patients with a history of substance abuse disorders) is also accumulating.16,17,18
Practical Prescribing (see Table)
Starting dose: Evidence and clinical common sense suggest short prescriptions, starting at the low end of the approved dose range.
Dose increases: Small increments and short therapeutic trials are rational. Patients should know within 1 week if a higher dose improves analgesia or worsens adverse effects. Encourage close family observation for somnolence, impaired thinking or coordination, and falls. Only conservative prescribing and a high index of suspicion can prevent delayed onset adverse effects – for example dental decay from reduced salivation, anticholinergic-induced delirium, or potentially increased dementia.
19,20 Dose reductions: As for other symptomatic treatment, consider dose reduction or deprescribing at every medication review. Some patients tolerate rapid dose decreases, which are prudent when adverse effects are potentially dangerous. However, withdrawal syndromes are known for all four drugs, occasionally serious. Gabapentin and pregabalin are drugs of abuse that can cause pharmacological dependence, increasing propensity for problematic withdrawal. Cyclobenzaprine’s elimination half-life of at least 1 day makes withdrawal less likely than from the other shorter-lived drugs. When deprescribing is not urgent, a practical office-based approach is to reduce dose over a few weeks. Identify the lowest effective dose, or deprescribe when appropriate.
Possible “evidence-informed dosing” for chronic pain
Conclusions
▪ Most patients do not obtain clinically meaningful pain relief at any dose of cyclobenzaprine, duloxetine, gabapentin, or pregabalin.
▪ High doses are unlikely to improve analgesia more than lower doses. They do increase harms.
▪ Clinical impacts of dose changes (good or bad) should usually be apparent within 1 week.
▪ Spontaneous improvement can appear to be a beneficial drug effect, even when it would have occurred without drug therapy. Try short therapeutic trials and periodic reassessment of patients whose pain improves during drug therapy.
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The draft of this Therapeutics Letter was reviewed by multiple experts and primary care clinicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
The Therapeutics Initiative is funded by the BC Ministry of Health. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
