Pregabalin Side Effects: What the Trial Data Actually Shows by Dose

Most pages about pregabalin side effects give you an undifferentiated list. Dizziness, drowsiness, weight gain, swelling, blurred vision, and so on down the page. What that format hides is the thing that actually matters, which is that nearly every one of these effects is dose dependent, and the difference between 75 mg per day and 600 mg per day is not small.

The FDA prescribing information contains the incidence tables from the controlled trials, broken out by dose. Those numbers are worth looking at directly, because they change how you think about the trade off between pain relief and tolerability.

Dizziness and drowsiness climb steeply with dose

These two account for most of why people stop taking pregabalin. Here is what the trials in diabetic peripheral neuropathy found, by daily dose:

Effect	75 mg/day	150 mg/day	300 mg/day	600 mg/day	Placebo
Dizziness	8%	9%	23%	29%	5%
Drowsiness	4%	6%	13%	16%	3%
Peripheral swelling	4%	6%	9%	12%	2%
Dry mouth	3%	2%	5%	7%	1%
Weight gain	0%	4%	4%	6%	0%
Blurred vision	3%	1%	3%	6%	2%

Read the dizziness row again. It roughly triples between 150 mg and 300 mg per day. That single jump explains why prescribers who titrate slowly get better adherence than ones who follow the label ceiling of moving to 300 mg within a week. Our pregabalin dosage guide sets out a slower titration schedule than the label permits.

The postherpetic neuralgia trials show the same shape at higher absolute numbers. Dizziness ran 11 percent at 75 mg per day, 18 percent at 150 mg, 31 percent at 300 mg and 37 percent at 600 mg, against 9 percent on placebo. Peripheral swelling went from essentially nothing at 75 mg per day to 16 percent at both 300 and 600 mg.

How many people actually stop because of side effects

Across all adult populations in the pre marketing controlled trials, 14 percent of people on pregabalin stopped early because of adverse effects, against 7 percent on placebo. The two leading reasons were dizziness at 4 percent and drowsiness at 4 percent.

In the diabetic neuropathy trials specifically the discontinuation rate was lower, 9 percent on pregabalin versus 4 percent on placebo, with dizziness at 3 percent and drowsiness at 2 percent leading. That difference partly reflects the lower dose ceiling used in that population.

Put simply, roughly one person in seven does not stay on pregabalin because of how it makes them feel, and the reason is almost always sedation rather than anything exotic.

The most common effects and what to do about them

Dizziness and drowsiness

These are worst in the first one to two weeks and after each dose increase, and they often ease as tolerance develops. Practical adjustments include weighting more of the daily dose toward the evening, holding at the current dose for longer before increasing, and not driving until you know how it affects you. The label carries a specific warning that pregabalin may impair the ability to drive or operate machinery.

Peripheral swelling

Swelling in the ankles and feet occurred in 6 percent of adults on pregabalin in controlled trials against 2 percent on placebo. In short term trials of people without significant heart or vascular disease there was no apparent link between this swelling and cardiovascular complications, and it was not associated with laboratory signs of kidney or liver deterioration.

The important interaction here is with thiazolidinedione diabetes medicines such as pioglitazone. The label notes higher rates of both swelling and weight gain when the two are combined than with either alone, which matters because diabetic neuropathy is a leading reason to be on pregabalin in the first place.

Weight gain

Weight gain appeared in about 4 percent of adults in controlled trials against effectively none on placebo, rising to 6 to 7 percent at 600 mg per day. Over months of continuous use it can be more noticeable than the short trial numbers suggest, and it is a common reason people ask to switch. In paediatric seizure trials, increased weight and increased appetite were the two most common adverse reactions.

Cognitive fog

The label groups this under thinking abnormal, which primarily covers difficulty with concentration and attention, and also includes slowed thinking and language problems. It ran 1 to 3 percent in the diabetic neuropathy trials, higher at 600 mg per day. Patients describe it more often than the trial numbers suggest, and it is worth raising as a specific complaint rather than accepting it as part of the deal.

Dry mouth and constipation

Both are dose related and both are manageable. Dry mouth ran up to 7 percent in the diabetic neuropathy trials and 15 percent at 600 mg per day in postherpetic neuralgia. Constipation reached 5 to 6 percent at higher doses.

The serious effects that need immediate attention

These are uncommon, but the response to each is to stop and get help rather than to wait and see.

Angioedema

Swelling of the face, mouth, tongue, lips, gums, throat or larynx has been reported both when starting pregabalin and during long term treatment. Some reports involved life threatening airway compromise requiring emergency treatment. The label instructs immediate discontinuation. Risk appears higher in people who have had angioedema before and in those taking ACE inhibitors, which are extremely common in the diabetic population that also takes pregabalin.

Hypersensitivity reactions

Skin redness, blisters, hives, rash, shortness of breath and wheezing have been reported shortly after starting. The instruction is the same: stop immediately.

Respiratory depression

This is the one that has attracted the most attention in recent years. Case reports, human studies and animal studies associate pregabalin with serious, life threatening or fatal respiratory depression when it is combined with other central nervous system depressants, particularly opioids, or when given to someone with existing respiratory impairment.

There is also more limited evidence linking pregabalin to serious respiratory depression without either of those factors present. The practical rule is that adding pregabalin on top of an opioid, a benzodiazepine or another sedating drug is a decision that needs to be made deliberately, with a low starting dose and someone watching.

Suicidal thoughts or behaviour

Antiepileptic drugs as a class, pregabalin included, raise this risk. A pooled analysis of 199 placebo controlled trials across 11 different antiepileptic drugs found roughly double the risk of suicidal thinking or behaviour, with an adjusted relative risk of 1.8 and a 95 percent confidence interval of 1.2 to 2.7.

The absolute numbers put that in proportion. The incidence was 0.43 percent among 27,863 people on an antiepileptic drug against 0.24 percent among 16,029 on placebo, an increase of roughly one case for every 530 people treated. The increased risk showed up as early as one week after starting. Anyone starting pregabalin should have someone around them who knows to watch for new or worsening depression or unusual changes in mood.

Effects that show up on tests rather than in symptoms

The label lists several that are picked up on monitoring rather than felt: creatine kinase elevations, decreased platelet count, PR interval prolongation on ECG, and ophthalmological effects. None of these are common, but they are the reason a prescriber may order bloodwork on long term treatment.

What abrupt stopping does

Stopping pregabalin suddenly is itself a source of adverse effects. Reported symptoms after abrupt or rapid discontinuation include insomnia, nausea, headache, anxiety, sweating and diarrhoea. In people taking it for epilepsy, abrupt withdrawal risks increased seizure frequency.

The label requires tapering over a minimum of one week. In practice, people who have been on higher doses for many months usually need considerably longer than that. Our guide to pregabalin withdrawal and tapering covers what a realistic schedule looks like.

How to reduce side effects without losing the benefit

• Start lower than the label allows. A few days at 75 mg at night before moving to 150 mg per day costs almost nothing and tells you a great deal.
• Titrate slower than one week. The label permits a move to 300 mg per day within seven days. Taking two or three weeks instead gives tolerance time to develop against the dizziness.
• Weight the dose toward the evening. If drowsiness is the limiting problem, an uneven split such as 75 mg in the morning and 150 mg at night often works better than an even one.
• Check kidney function before assuming a standard dose is right. Pregabalin is cleared almost entirely by the kidneys, so an unrecognised drop in clearance raises blood levels and every dose related side effect along with them. This is the most common avoidable cause of intolerable effects.
• Do not chase the ceiling. For diabetic neuropathy the label is explicit that 600 mg per day gave no meaningful extra benefit over 300 mg and was tolerated worse. More is not better past a point.
• Review every sedating medicine you take. Opioids, sleep aids and sedating antihistamines all stack with pregabalin.

Our pregabalin dosage guide sets out the labelled ceilings by indication and what renal adjustment involves.

When a different drug is the answer

If a properly titrated dose has been given a fair trial of two to four weeks at 300 mg per day and either the pain relief is inadequate or the side effects are not settling, switching is a reasonable conversation. Gabapentin is the closest alternative and behaves differently in ways that occasionally suit people who could not tolerate pregabalin. A pharmacokinetic and pharmacodynamic comparison of the two (PMID 20818832) sets out where they diverge, and our pregabalin versus gabapentin comparison covers the practical differences.

The wider set of options for nerve pain is covered on our chronic pain page.

References

• FDA prescribing information for pregabalin capsules, section 6.1 (Clinical Trials Experience), including Table 4 for diabetic peripheral neuropathy and Table 5 for postherpetic neuralgia
• FDA prescribing information, sections 5.1 (Angioedema), 5.2 (Hypersensitivity), 5.3 (Suicidal Behavior and Ideation), 5.4 (Respiratory Depression), 5.6 (Abrupt or Rapid Discontinuation) and 5.7 (Peripheral Edema)
• DailyMed label for pregabalin capsules, adverse reactions section
• Bockbrader HN et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. PMID 20818832

Medical disclaimer: this article is for information only and is not medical advice. If you develop swelling of the face, mouth or throat, difficulty breathing, or a spreading rash while taking pregabalin, seek emergency care. Talk to your prescriber before changing or stopping any prescribed medicine. If you are having thoughts of harming yourself, contact your doctor or a crisis line in your country right away.