Gabapentin for dogs
Neurogenic pain is inherent in a functional lesion of the central or peripheral nervous system and is opposed to nociceptive pain by its physiopathological mechanisms and therapeutic management. gabapentin, eliminated exclusively by the kidneys and not interfering with the metabolism of other drugs, has been used for nearly ten years in the treatment of epilepsy. The use of gabapentin in the treatment of neuropathic pain is more recent: the benefit of gabapentin in this indication has been confirmed by four randomized controlled studies based on "models" of peripheral neuropathic pain such as diabetic polyneuropathy and post-zosterian neuralgia. The magnitude of the therapeutic effect and the incidence of adverse events of gabapentin are comparable to amitriptyline. Gabapentin, however, is still better tolerated than tricyclic antidepressants. However, the therapeutic gain of gabapentin must be somewhat balanced by a significantly higher cost than other proven therapies.
Neurogenic or neuropathic pain is caused by injury or functional impairment of the central or peripheral nervous system.
Neuropathic pain can be the result of multiple etiologies. They concern hereditary or acquired neurological disorders such as metabolic (diabetic), infectious (post-zosterian, HIV), or more rarely those inherent in monoclonal gammopathy, paraneoplastic syndrome or as a consequence of toxic (alcohol, etc.) or ischemic injuries.1 While additional investigations (e. g. glycated Hb, anti-HU antibodies, c-ANCA, FR, HIV, HCV, electroneurography, electromyography) sometimes make it possible to identify a potentially treatable etiology, neurogenic pain often remains an uncontrollable pain situation. They are opposed to pain "by excess nociception", due to physiopathological mechanisms and their distinct symptomatic therapeutic management.
In addition to etiological treatment, which remains the rule, targeted symptomatic treatment is often necessary. An insufficient analgesic response to standard treatments, such as NSAIDs, paracetamol and most opiates, is a particular feature of this painful syndrome.
To approach it, the introduction of drugs modulating the activity of the nervous system has often involved substances of the anticonvulsant or antidepressant type, whose therapeutic range is often narrow, particularly when one considers introducing them into the elderly or multi-medicated people.
In recent years, analgesics with an improved safety profile and reduced interaction potential have been identified. This article examines the clinical evidence for the efficacy and safety of gabapentin in selected peripheral neuropathic pain syndromes. Gabapentin has been registered in the United States since 1994 for the treatment of refractory comet attacks with or without generalization and administered in combination with a background antiepileptic. Its efficacy in the treatment of neuropathic pain was first reported in 1996 in an uncontrolled open observation of follow-up of patients with neuropathic pain refractory to conventional therapies.2 Subsequently, some authors reported a beneficial effect in two patients with ciguatera, a neurotoxin present in some fish in warm seas causing mainly damage to the peripheral nervous system and particularly resistant to conventional analgesics.
In order to validate the indication of gabapentin for the symptomatic treatment of neuropathic pain, several randomized controlled pivotal studies were initiated using conventional models of neurogenic pain, such as diabetic neuropathy and post-zosterian pain.
ANALGESIC MECHANISM OF ACTION
Although gabapentin is a structurally related molecule to the neurotransmitter GABA, it does not have intrinsic agonist or gabaergic antagonist activity and its mechanism of action is not fully understood. Unlike first-generation antiepileptics such as phenytoin or carbamazepine used in the treatment of neuropathic pain, gabapentin does not interfere by blocking sodium channels.
In experimental models of peripheral neurological injury in animals, gabapentin reduces painful behavior and signals and improves tolerance to tactile and thermogenic stimuli.4 In this model, the analgesic effect of gabapentin is mediated
A prospective, crossover, double-blind, randomized study involving 21 patients with neurogenic pain on diabetic polyneuropathy compared the efficacy of gabapentin (median dose 1565 mg/d) to amitriptyline (median dose 59 mg/d) over a six-week follow-up period based on daily pain scores. The results did not reveal a superiority of one treatment over the other, both with a similar amplitude of effect up to six weeks. Given the modest collective, the power of this study remains insufficient to highlight the smaller differences between these two molecules.
With the exception of xerostomia, weight gain (amitriptyline > gabapentin) and vertigo (gabapentin > amitriptyline), the frequency and severity of adverse events were comparable.
Authors compared their results to a systematic review of the literature evaluating the efficacy of tricyclic antidepressants and antiepileptics in the management of neurogenic pain: the assessment of efficacy and safety was compared through their respective NNT ("number needed to treat") and NNH ("number needed to harm").
The NNT is defined as the number of patients to be treated so that a patient benefits from a more than 50% reduction in pain compared to the situation without treatment (control group). NNH is defined as the number of people who need to be treated for an individual to experience an adverse event compared to a placebo. If treatment increases the incidence of an adverse event, it will result in a lower NNH. For randomized controlled trials with amitriptyline, NNTs between 1.9 and 4.1 were calculated versus an NNT of 3.2 for gabapentin. With regard to the occurrence of minor AEs, NNHs range from 1.7 to 8.8 for amitriptyline versus 3.7 for gabapentin; for so-called major adverse events, i.e., leading to discontinuation of treatment, NNHs of 13 to 37 are reported for amitriptyline versus 25 for gabapentin. The greater variability of NNT and NNH for amitriptyline is explained by a greater number of studies available with a clinical follow-up of twenty years of use.
It should be recalled that the margin of safety of tricyclic antidepressants (pharmacokinetic variability with the risk of interactions, rhythm disorders, weight gain, anticholinergic effects) reduces their margin of maneuver and patients' moderate appreciation of them significantly reduces therapeutic compliance.
For the treatment of post-Zosterian pain, gabapentin can thus be compared to amitriptyline both in terms of efficacy and safety and with fewer formal contraindications.
Gabapentin and neurogenic pain of various etiologies To be closer to populations potentially likely to receive gabapentin in clinical practice, a fourth randomized controlled trial included 305 patients, 153 on gabapentin and 152 on placebo. This study evaluated the benefit of the antiepileptic when administered in neuropathic pain of various etiologies. A qualitative assessment of the symptoms and signs made it possible to assess the impact of gabapentin in a more detailed way. Thus, each patient had to have at least two of the following symptoms: allodynia (69%), burns (80%), fulgurating pain (86%) and hyperalgesia (71%) in order to participate, regardless of the etiology and location of the pain.
The standard dose was set at 900 mg/d, but in the event of an insufficient response (at least 50% reduction in painful symptomatology required), successive titration up to 1800 mg/d (12.4%) or even up to 2400 mg/d (66% of the collective) was allowed until the end of the fourth week. The primary objective was to modify weekly mean pain scores and was associated with other symptomatic secondary endpoints such as allodynia, burns, fulgurating pain, and hyperalgesia, as well as indirect assessment measures using questionnaires.
A decrease in the score of 1.5 (from 7.1 to 5.6, 21%) was observed on the VAS compared to a decrease of 1 (7.3 to 6.3, 14%) for the placebo. This difference, although statistically significant (p = 0.048), remains clinically modest.
Nevertheless, there was a significant difference for the quality of life questionnaire, pain characteristics (McGill), patient subjective impression, clinical impression of the physician and for burn and hyperalgesia symptoms during weeks 1 to 6. On the other hand, this difference disappears during the last assessment at week 8, for symptoms such as allodynia.