Which medication can be increased in dose first, pregabalin (anticonvulsant) or amitriptyline (tricyclic antidepressant), in a patient with fibromyalgia?

From the Guidelines

In a patient with fibromyalgia, pregabalin can be increased in dose first, as it is generally better tolerated and has a more straightforward titration schedule compared to amitriptyline. According to the study published in the Mayo Clinic Proceedings 1, the recommended dosing for pregabalin starts at 50 mg three times daily or 75 mg twice daily, and can be increased to 300 mg/d after 3-7 days, then by 150 mg/d every 3-7 days as tolerated, with a maximum dose of 600 mg/d.

Key Considerations for Dose Escalation

• Pregabalin has linear pharmacokinetics, making its dosing more straightforward compared to other medications like gabapentin.
• The study suggests that most patients can start taking pregabalin at 150 mg/d in 2 or 3 divided doses, which is then titrated up to 300 mg/d after 1 or 2 weeks.
• For patients who tolerate 300 mg/d but have inadequate pain relief, the dosage can be further titrated to 600 mg/d, although higher dosages are not consistently more effective than 300 mg/d and are associated with a greater rate of adverse effects.

Comparison with Amitriptyline

• Amitriptyline, a tricyclic antidepressant, requires slower titration due to its anticholinergic side effects and potential cardiac concerns, starting at 25 mg at bedtime and increasing gradually by 25 mg every 3-7 days as tolerated, with a maximum dose of 150 mg/d.
• The slower titration of amitriptyline is necessary to minimize side effects such as dry mouth, constipation, urinary retention, sedation, and orthostatic hypotension.

Clinical Decision

Given the patient's current regimen of pregabalin 150 mg three times a day and amitriptyline 50 mg daily, pregabalin can be considered for dose escalation first, given its more favorable side effect profile and direct mechanism of action for pain modulation in fibromyalgia, as supported by the study 1.

From the FDA Drug Label

The recommended dose of pregabalin for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Initial Dosage for Adults For outpatients, 75 mg of amitriptyline HCl a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg per day

The patient is currently taking pregabalin 150 mg three times a day (450 mg/day), which is within the recommended dose range for fibromyalgia. The patient is currently taking amitriptyline 50 mg daily, which is below the usual maintenance dosage of 50 to 100 mg per day. Considering the current doses, amitriptyline can be increased in dose first, as the patient is currently taking a lower dose than the recommended maintenance dosage. Pregabalin is already at a dose within the recommended range, and increasing it further may increase the risk of dose-dependent adverse reactions. 2 3

From the Research

Medication Dose Increase for Fibromyalgia

• The patient is currently taking pregabalin 150 mg three times a day and amitriptyline 50 mg daily for fibromyalgia.
• According to the study 4, duloxetine 120 mg was associated with the highest improvement in pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.
• The study 5 compared the effectiveness of amitriptyline and pregabalin in fibromyalgia patients and found that both drugs improved pain, fatigue, sleep disorder, disability, psychological evaluation, and cognitive function, but amitriptyline was more effective at reducing experimentally measured pain than neuropathic pain.
• The study 6 investigated the combined use of pregabalin plus paroxetine, amitriptyline, or venlafaxine for fibromyalgia management and found that the combined use of pregabalin plus paroxetine resulted in significantly lower Somatic Symptoms Scale-8 and Center for Epidemiological Studies Depression Scale scores, higher medication tolerability, and improved life satisfaction, mood, and sleep quality.
• The study 7 found that duloxetine, milnacipran, and pregabalin had moderate/good evidence of substantial pain relief for 4-12 weeks in around 1 in 10 adults with moderate or severe FMS pain, without evidence of efficacy beyond six months.
• Based on the study 4, it can be suggested that the dose of pregabalin can be increased up to 300 mg or 450 mg, as these doses were compared in the study and found to be effective in reducing fibromyalgia symptoms.
• However, the study 8 found that the dose of the medications was not increased in most patients during the follow-up period, and only one-fifth of patients continued the treatment for ≥1 year.
• Therefore, the decision to increase the dose of either pregabalin or amitriptyline should be based on the individual patient's response to treatment and the presence of any adverse effects, as suggested by the studies 4, 5, 6, 7.