This article is more than 5 years old. Information may no longer be current.
Gabapentin effective for chemotherapy-induced nausea
The most common adverse effects seen with gabapentin included somnolence and dizziness, both of which were dose related.
The emetic response to chemotherapy is complex and involves several organs as well as multiple neurotransmitters. Signals are received from various parts of the brain and the gastrointestinal tract, and are then coordinated in the vomiting center. The vomiting center then triggers the emetic response in the effector organs.
|
|
The primary neurotransmitter receptors involved in this process are serotonin (5-hydroxytryptamine type 3), dopamine and neurokinin-1 receptors. Other neurotransmitters include acetylcholine, corticosteroids, histamine, cannabinoid and opiates. The roles of additional neurotransmitters are likely to be further defined.
Successful prevention of chemotherapy-induced nausea and vomiting requires the use of combinations of antiemetics because no single pharmacologic agent can inhibit the action of all these neurotransmitters. Modern antiemetic regimens for moderately to highly emetogenic chemotherapy regimens contain a serotonin antagonist, a corticosteroid and often the neurokinin-1 antagonist, aprepitant (Emend, Merck). Unfortunately, even with these multi-agent combinations, some patients still suffer from nausea and vomiting in the acute phase (the first 24 hours) and especially in the delayed phase (after the first 24 hours.) Alternative medications are being studied for use in chemotherapy-induced nausea and vomiting, including olanzapine (Zyprexa, Lilly) and gabapentin (Neurontin, Pfizer).
Usage of gabapentin
Gabapentin was first developed as an anticonvulsant agent and is useful in several different seizure types. In addition, it has activity in other neurological disorders, such as painful diabetic neuropathy, post-herpetic neuralgia, bipolar disorder and migraines.
In patients with cancer, gabapentin is widely used to treat neuropathic pain and has shown some activity in reducing vasomotor hot flashes in patients with breast cancer. Two recent reports describe the antiemetic actions of gabapentin.
Gabapentin is an analog of gamma-aminobutyric acid but does not bind to GABA-A or GABA-B receptors and does not affect the synthesis, uptake or metabolism of GABA. The action of gabapentin seems to be associated with certain voltage-dependent calcium channels, which may control the release of excitatory neurotransmitters associated with epileptogenesis and nociception.
The dose of gabapentin as an anticonvulsant starts with 300 mg orally three times daily and can be increased to 600 mg orally three times daily, although total daily doses of up to 2,400 mg can be used. The dose need for neuropathic pain is usually lower, starting with 100 mg orally three times daily and ranging up to 600 mg orally three times daily.
Absorption of gabapentin is saturable, with the bioavailability of lower doses being higher than that with higher doses. It has a fairly low volume of distribution and little plasma protein binding. It is eliminated by the kidney, and the clearance of gabapentin is reduced in patients with reduced renal function. The dose should be reduced appropriately for these patients according to their estimated creatinine clearance to avoid excessive central nervous system adverse events. It is removed by hemodialysis.
The most common adverse effects seen with gabapentin include somnolence and dizziness, both of which are dose related. Other common adverse events include ataxia, nystagmus, fatigue, confusion, tremor and headache.
One group of researchers (Guttouso et al) studied the effect of gabapentin following the case of a patient whose persistent nausea and vomiting after chemotherapy treatment resolved when gabapentin was added to control hot flashes.
Subsequently, a non-controlled trial was undertaken in nine patients with breast cancer who had level-four nausea (on a one to seven scale) was undertaken. These patients were assigned to a chemotherapy regimen containing doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every three weeks for four cycles. All patients were assigned a routine antiemetic regimen with ondansetron (Zofran, GlaxoSmithKline) and dexamethasone (Decadron, Merck), and some patients were also assigned lorazepam.
Rescue medications of ondansetron, prochlorperazine and/or dexamethasone were offered. Nausea was assessed by use of a nausea diary that the patients completed. The gabapentin treatment was started five days before chemotherapy as 300 mg orally every night for two days, 300 mg orally twice daily for two days, 300 mg orally three times daily for six days and then stopped on the sixth day after chemotherapy.
Seven of the nine patients experienced a reduction in the peak nausea score for the acute chemotherapy-induced nausea and vomiting stage. One patient’s peak score stayed at zero and one patient’s score increased. Eight of nine patients had a drop in the peak delayed-phase nausea score; one patient’s score increased. The majority of the patients showed a dramatic effect with gabapentin, with a median of a three-point (out of seven) drop in both the peak nausea score and the acute nausea score for both the acute and delayed phase. All patients, except for the one patient who did not respond, preferred the gabapentin-containing antiemetic regimen to the regimen in their first cycle of chemotherapy.
Two of the nine patients experienced mild-to-moderate drowsiness that did not require dosage reductions. The protocol allowed for a dosing increase to 600 mg orally three times daily in the third/fourth cycle for patients who still had nausea and vomiting, and these three patients did not have increased adverse events.
Patient diaries
Another group of researchers (Menendez-Leal et al) has also studied the effect of gabapentin in chemotherapy-induced nausea and vomiting. They enrolled 24 patients (92% women) who had moderate-to-severe nausea and vomiting with previous cycles of chemotherapy. The chemotherapy contained cyclophosphamide/doxorubicin (n=15), cisplatin (n=5), and other regimens (n=4). All patients received a 5-HT3 receptor antagonist and dexamethasone. Nausea and vomiting was assessed by the patient with a diary completed three times daily for five days.
Gabapentin was administered in the following dose regimen: 300 mg orally on day two, 300 mg orally twice daily on day one, then 300 mg orally three time daily for five days. In the acute phase (day 1), 58% of patients had no emesis, and 75% had no/mild nausea. In the delayed phase of days two to five, 75% to 92% (depending on the day) of patients had no emesis, and 79% to 92% had no/mild nausea. Unfortunately, these results have been published only in abstract form, and it is not clear if data was available from the previous cycles or if there were prior data that were not published due to space limitations. With the data presented, it is not possible to ascertain if gabapentin improved the patients’ nausea and vomiting, although the researchers concluded that gabapentin has activity in this setting.
Multiple neurotransmitters are involved in the emetic response to chemotherapy. Additional and novel antiemetics are needed for those patients who have an inadequate response to recommended antiemetic regimens. The use of gabapentin would exploit new neurotransmitters that may be involved in the signaling of nausea and vomiting. Further studies exploring the activity of gabapentin in preventing chemotherapy-induced nausea and vomiting are warranted.
For more information:
- Lisa K. Lohr, PharmD, BCPS, BCOP, is Clinical Leader of Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center, Fairview. She is also the Pharmacology section editor of Hem/Onc Today.
- Guttuso T Jr, Roscoe J, Griggs J. Effect of gabapentin on nausea induced by chemotherapy in patients with breast cancer. Lancet. 2003;9370:1703-1705.
- Menendez-Leal A, Quijano C, Menendez-Rivera AG. Prophylaxis of delayed chemotherapy induced nausea and vomiting with gabapentin. Support Care Cancer. 2006;14:600.