Does gabapentin really provide analgesia or does it just make my patient sleepy?
Guest article by Tamara Grubb, DVM, PhD., DACVAA
Like most chronic diseases, chronic pain associated with osteoarthritis can be very difficult to treat. Chronicity increases the disease complexity and alters the potential sources of pain. Because of the altered/increased number of sources, multimodal therapy – with a focus on treatments with different mechanisms and sites of action – is almost always necessary for effective analgesia, especially if the pain is moderate to severe. Among the drugs in the chronic pain formulary is gabapentin, which is commonly dispensed, but not always apparently effective. Because gabapentin can also be sedating, a common question arises: ‘does gabapentin really provide analgesia or does it just make the patient sleepy?’ If it does both, that could be beneficial for night-time doses of the drug in patients with pain and difficulty sleeping. But sedation without pain relief could lead to a patient that is unable to exhibit signs of pain, with subsequent failure to relieve pain. This is a very valid and important question, and the answer requires some understanding of the drug.
Mechanism of action
Gabapentin blocks presynaptic voltage-gated calcium channels on nerves in the central nervous system, including the spinal cord. This decreases presynaptic calcium influx and subsequently leads to a decreased release of excitatory neurotransmitters from the presynaptic membrane, including neurotransmitters involved in the propagation of pain. Gabapentin may also have inhibitory effects at peripheral nerves and at N-methyl-D-aspartate (NMDA) receptors, which are integral to the development of central sensitization. Thus, scientifically, gabapentin should provide analgesia and is in fact approved in humans for the relief of postherpetic neuralgia, a type of neuropathic pain.
However, the clinical analgesic efficacy of gabapentin is known to be variable, as experienced by virtually everyone prescribing the drug for pain relief. This variability, which should not preclude the use of gabapentin in an analgesic protocol, is caused by a number of factors, including the potency, pharmacokinetics, and dosing of the drug, as well as the type of pain experienced by the patient. Understanding these factors, and using the drug appropriately, can potentially improve gabapentin-mediated analgesia.
Factors impacting analgesic efficacy
Analgesic potency is the first factor to consider. Drugs like non-steroidal anti-inflammatory drugs (NSAIDs) and the new (already released in some countries but not yet in the US) anti-nerve growth factor monoclonal antibodies (antiNGF mAbs) decrease pain at its initiation, which is the transduction phase of the pain pathway. This is a very powerful mechanism of action. Preventing/decreasing pain at its source also prevents/decreases the development of peripheral and central sensitization, both of which can, unfortunately, amplify the level of pain that the patient experiences. The mechanism of action and the potency of these drugs provide pain relief in the vast large majority of patients.
Conversely, when the pain signal reaches the modulation phase of the pain pathway in the spinal cord, pain can be very difficult to control because of the widely varied and potent mechanisms of pain propagation and amplification that occur in this phase. Pain relief mediated here is often less profound and the effects may not be as obvious since the pain may now have multiple active sources, all of which may need different types of analgesic treatment.
Currently available drugs with activity at this phase of the pain pathway, like gabapentin, cannot provide the same profound and consistent level of pain relief as provided by NSAIDs and antiNGF mAbs when used alone.
The next factors to consider are gabapentin pharmacokinetics and the subsequent impact on dosing, both of which can impact analgesic efficacy. In humans and presumably in dogs and cats, the drug undergoes nonlinear pharmacokinetics. After oral administration, the drug is absorbed from the gastrointestinal tract via a saturable transport system, leading to a variable bioavailability and a gabapentin serum concentration that does not increase linearly with increasing drug doses (ie, nonlinear pharmacokinetics). The bioavailability of gabapentin administered to humans roughly (there is a great deal of individual variation) decreases from 60% to 33% as the dose increases from 900 to 3600 mg/day. This leads to analgesic gabapentin dosages that are variable between patients and to the fact that the dosages may need to escalate to a greater degree than expected to reach an effective serum concentration.
Unfortunately, without knowledge of the nonlinear pharmacokinetics, many veterinarians are uncomfortable dosing the drug ‘to effect’ at seemingly excessively high doses. This has complicated not only clinical analgesic therapy but also the results of research studies. There are few published gabapentin analgesic studies in animals. Of those that do exist, most that failed to show gabapentin efficacy studied doses of 5 mg/kg administered q12 hours.
A dose of 10 mg/kg is likely the minimum effective dose in most healthy patients and the pharmacokinetics for both dogs and cats indicate that gabapentin should be administered every q6-8 hours to achieve analgesia. Even this dose may be ineffective and should be escalated if no pain relief occurs in 3-7 days (depending on the degree of pain and patient health). The myth that gabapentin takes several weeks to have an effect is likely based on underdosing. A caveat to high dosing is that in aged patients or those that might clear the drug slowly (ie, patients with hepatic or renal disease), a starting dose of 3-5 mg/kg q12 hours and slow escalation (every 7-10 days) is recommended (see more in the ‘safety’ section). Step-by-step dosing/dose-escalation guidelines are available in an open-access paper
Finally, the type of pain that the patient is experiencing has a major impact on analgesic variability. Most sources/types of pain, like surgical or trauma pain, start with inflammation. Many drugs, including gabapentin, do not control the pain of inflammation and thus are ineffective if inflammation is the sole source of pain. However, if the inflammation is sustained, severe, and/or un- or under-controlled, peripheral and central sensitization are likely to occur and can cause changes in the pain pathway that is, or mimics, neuropathic pain. This type of pain is very complex and difficult to treat and can be a component of both acute and chronic pain. Examples include a moderate to severe traumatic injury for acute pain and moderate to severe osteoarthritis for chronic pain. In these situations, gabapentin is likely to provide at least some analgesia by decreasing the pain in the spinal cord at the modulation phase of the pain pathway. Gabapentin may also be effective in patients with preexisting pain undergoing seemingly minorly painful procedures. This can cause acute-on-chronic pain which often results in central sensitization.
Safety
The primary gabapentin-mediated side effect is sedation, which is not necessarily an adverse effect if sedation is desired, as in the previously mentioned patient that might have difficulty sleeping at night. Day-time sedation is rarely desired – but sedation may be confused with a patient that is taking more ‘naps’, which can be beneficial. The difference is important to discern and the owner should be asked if the pet seems ‘groggy’ all day or takes frequent naps but is very active between naps. The latter situation likely indicates that the patient has lower pain levels and can rest more comfortably – and play more comfortably. Anxiolysis can also be achieved with gabapentin and could potentially be confused with sedation. Again the difference is important to discern since anxiolysis is beneficial in alleviating pain. Pain can obviously cause anxiety and anxiety can exacerbate the level of pain that the patient is experiencing.
Sedation is primarily dose-related and is generally alleviated by dose-reduction. Interestingly, if sedation occurs and the dose is reduced, the dose can often be re-increased slowly (if necessary) without the occurrence of sedation. Sedation is more common in patients receiving other potentially sedating drugs (eg, Trazadone). Dose-dependent ataxia and weakness can occur, especially in older large-breed dogs with decreased muscle strength. Gabapentin is cleared by the kidneys and somewhat by the liver (at least in dogs) and can more rapidly accumulate in patients with renal or hepatic disease/insufficiency, potentially leading to a more rapid onset of adverse effects. As previously described, a lower starting dose and slower dose escalation is recommended for these patients. Gabapentin is a DEA-controlled drug in some states and, unfortunately, is a drug that has been diverted for human abuse.
Pregabalin
Pregabalin, which has the same mechanism of action as gabapentin, is approved for numerous neuropathic pain conditions in humans. Compared to gabapentin, pregabalin has a greater affinity for the voltage-gated calcium channel on the presynaptic membrane, which may lead to greater analgesic efficacy. In addition, pregabalin does not depend on a transport system for intestinal absorption and its pharmacokinetics are linear (‘first order’) in humans and presumed linear in dogs and cats. This leads to more predictable dose-related effects. Safety concerns are the same as those for gabapentin. Pregabalin is a DEA Class IV drug and controlled in all states. There are few dosing studies in veterinary medicine but those available suggest a starting dose of 4 mg/kg q12h in the dog and 1-2 mg/kg q12h in the cat. Sedation occurred with 4 mg/kg in cats.
Where does that leave the use of gabapentin and/or pregabalin for analgesia?
- Consider the pain source and use gabapentin or pregabalin as part of a multimodal protocol in patients that may have or may develop neuropathic pain.
- Start at a standard dose of gabapentin (usually 10 mg/kg q8 hours in a healthy moderately painful patient) and be prepared to alter that dose to provide analgesia while avoiding sedation. An open-access flow chart is published and will be helpful to determine the starting dose and when/how to decrease/increase the dose https://todaysveterinarypractice.com/gabapentin-and-amantadine-for-chronic-pain/.
- If using pregabalin, until more research is available, dose at 4 mg/kg q12h in the dog and 1-2 mg/kg q12h in the cat.
- To avoid owner-mediated drug cessation at the first sign of sedation, communicate with the owner about effects/adverse effects so they understand that sedation may occur, but can be alleviated with dose reduction.
- Consider more frequent naps with increased activity when awake as a good thing. Sedation is not necessarily a good thing unless used to enhance sleep. Anxiolysis is another good thing, especially in patients with pain.
- Be cautious about which clients are prescribed these drugs for their pets and follow controlled drug laws for your region.
References
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