The absorption characteristics of gabapentinoids differ markedly. Gabapentin demonstrates saturable absorption. Its bioavailability decreases from 60% to 33% as its dosage is increased from 900mg/day to 3,600mg/day. This property results in non-linear changes in plasma concentration within its clinical dosage range. In contrast, pregabalin's absorption is non-saturable and bioavailability is high (≥ 90%) throughout its dosage range. 1
Gabapentin shows a ceiling of clinical effects at higher doses both when examined in post-herpetic neuralgia 1 and in seizure disorders, 1, 2 with effects plateauing above 1,800mg/day. These data suggest that gabapentin can be tapered relatively quickly at dosages higher than 1,800mg/day but when below 1,800mg/day, gabapentin should probably be tapered more cautiously. This is reflected in the gabapentin-specific tapers presented in this chapter.
Although the major approach outlined in the drug-specific sections involves making reductions every 2-4 weeks (sometimes called 'cut and hold') 3 an alternative approach is called micro-tapering, whereby a small change in dose is made each day. Theoretically (see Figure 3.4) making smaller reductions should produce smaller disruptions of the homeostatic equilibrium leading to less intense withdrawal symptoms. 4 In practice, this process might require further dilutions of a liquid version of the drug and the use of small-volume syringes. It also requires quite complex calculations and record keeping. Micro-tapering allows the patient great flexibility in finding a rate of reduction that is tolerable for them. Where several doses of a medication are taken each day, these same small dose reductions can be made to all doses, or sequentially to one dose at a time (e.g. morning, afternoon or night).
Micro-tapering rates can be calculated from the regimens given in the drug-specific sections by dividing the change in dose for each step by 14 or 28 days, depending on the rate of desired taper. For example, if a regimen suggests that a reduction should be made from 3,600mg per day to 2,400mg per day in one step over 4 weeks then this could be converted into a reduction of 40mg each day for approximately 4 weeks. For example, 40mg per day reductions could be implemented using the manufacturer's 50mg/mL solution of gabapentin by reducing the volume taken from 72mL (3,600mg) per day by 0.8mL each day. If the drug is taken several times a day these daily reductions can be divided between the different doses. As the size of the reductions made diminishes the rate of tapering per day will also reduce - for example, a reduction from 125mg to 100mg over 4 weeks would involve a reduction of approximately 1mg per day. This rate can be slowed if withdrawal symptoms become too unpleasant.
There is little research into adjunctive medications used in assisting gabapentinoids tapering. Currently there are no medications approved by the FDA or other drug regulators to alleviate the symptoms of withdrawal from gabapentinoids. Pharmacological adjunctive treatments for other dependence-forming medications such as benzodiazepines have had mixed reviews. 5, 6 Many drugs that have been trialled to help people with withdrawal symptoms from dependence-forming medications themselves cause physical dependence and withdrawal. 6 Ultimately these agents may then in turn need to be tapered, and are associated with their own adverse effects. 7 Clearly then, using a dependence-forming agent to assist withdrawal is ultimately likely to be self-defeating. The NICE guidance on safe withdrawal of dependence-forming medication states explicitly 'Do not treat withdrawal symptoms with another medicine that is associated with dependence or withdrawal symptoms.' 8 The advice of the British National Formulary (BNF) as regards benzodiazepines may be relevant: 'The addition of beta-blockers, antidepressants and antipsychotics should be avoided where possible.' 9
When severe withdrawal symptoms occur it is generally preferable to slow the rate of taper to minimise withdrawal symptoms rather than seek to mask them with another medication. In case studies the drug most effective at resolving withdrawal symptoms from gabapentinoids was the original gabapentinoid (successful in 18 out of 18 cases recorded). 10 In case studies of patients suffering from gabapentinoid withdrawal 7 out of 8 patients who were treated with an adjunctive benzodiazepine (including 2 cases where haloperidol was used in addition to a benzodiazepine) did not experience control of their withdrawal symptoms. 10 The addition of another medication also risks complicating the picture by adding in new adverse effects, and potential interactions with existing medication. In the process of withdrawal, some patients will become sensitised to a range of medications, which may include other psychiatric agents. 7, 11 This is another reason that a cautious approach should be taken to the introduction of new agents. 7, 11
In some cases of severe withdrawal, the addition of an adjunctive medication might be considered. 12 The adjunct agent should be ideally one without a strong withdrawal syndrome and with less severe adverse effects than the original gabapentinoid. Drugs like propranolol 13, 14 and antihistamines like hydroxyzine 15 have been used in case of unpleasant withdrawal symptoms for benzodiazepines, with inconclusive findings. These drugs might be considered in difficult cases of gabapentinoid withdrawal. 16 Ideally these agents should be used only for the short term, given the risk of physical dependence and withdrawal with chronic use. 17
There has been almost no formal research into the effects of supplements on withdrawal symptoms from gabapentinoids. Any theories on the possible benefits of supplements in this area are mere speculation. Hypersensitivity to adverse effects may also be seen with supplements when used for patients in withdrawal from other dependence-forming medications, such as benzodiazepines, which may relate to gabapentinoid withdrawal as well, 18 so a cautious approach should be employed.