Is there evidence supporting the concomitant use of pregabalin and gabapentin for the management of pain?

Is there evidence supporting the concomitant use of pregabalin and gabapentin for the management of pain?

Comment by InpharmD Researcher

Limited data mainly derived from case reports and a retrospective review has reported successful management of neurologic pain and pruritus when administering combination overlap of gabapentin and pregabalin. However, one case report described intolerable adverse events due to the gabapentinoid therapeutic duplication. Since both agents have the same mechanism of action and pharmacodynamic targets, reviews do not routinely recommend dual gabapentinoid therapy.

Background

A proposed mechanism of action of pregabalin and gabapentin is antagonism of NMDA receptors. Both drugs can also antagonize calcium channels in the central nervous system. Despite their similarities, they have been used in combination in both clinical and research situations, and have been noted to have a synergistic effect in pain control without concern for clinically significant pharmacokinetic interactions. [1]

Other reviews on treating neuropathic pain do not recommend a combination of pregabalin and gabapentin. They do advocate one of these agents in combination with medications that have other mechanisms of action (e.g. tricyclic antidepressants, SNRIs, SSRIs, opioids, other antiepileptics). [2], [3]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there evidence supporting the concomitant use of pregabalin and gabapentin for the management of pain?

Please see Tables 1-3 for your response.

Is there a role for combined use of gabapentin and pregabalin in pain control? Too good to be true?
Design	Case report
Case presentation	A 76-year-old woman with end-stage metastatic renal carcinoma was admitted to the palliative care unit. The patient was experiencing neuropathic pain in the back and hip area, which were not alleviated with oral hydromorphone and 150 mg pregabalin BID prior to admission. The use of serotonin, norepinephrine reuptake inhibitors, and opioids did not relieve pain. Nightly oral dose of gabapentin 100 mg while titrating pregabalin down to 150 mg daily observed significant improvement in pain control, which eventually resolved while allowing further dose reduction of pregabalin over a three-week period. When the oral pregabalin dose was at 25 mg daily, minimum pain activity was again observed. The oral dose of gabapentin was increased to 100 mg BID while maintaining 25 mg pregabalin daily, and the pain subsided once more. No adverse events were observed with overlapping the two medications, and attempts to discontinue pregabalin reintroduced the pain even with further increase of the gabapentin dose.
Study Author Conclusions	The combined use of gabapentin and pregabalin represents a valuable addition to the therapeutic resources of neuropathic pain and inflammatory nociception. Research into the combined use of these agents is seriously lacking. Further studies are needed to establish synergy and propose conversion scales.

References:
[1] Senderovich H, Jeyapragasan G. Is there a role for combined use of gabapentin and pregabalin in pain control? Too good to be true?. Curr Med Res Opin. 2018;34(4):677-682.

Potential Adverse Consequences of Combination Therapy with Gabapentin and Pregabalin
Design	Case report
Case presentation	A 57-year-old female patient with well-controlled type 2 diabetes mellitus (DM) and hypertension presented to the community pharmacy complaining of fatigue, drowsiness, and dizziness for the past 2 weeks. Her current medication list included metformin 500 mg TID, gliclazide MR 30 mg BID, ramipril 5 mg once daily, and gabapentin 100 mg TID and recently started pregabalin 25 mg BID. With a 5-year history of DM, the patient developed loss of sensation in the periphery and numbness and tingling in the hands and feet, and was initiated on gabapentin 100 mg once daily three months ago (titrated up to the current dose). Due to unsatisfied response to the gabapentin regimen, the patient's primary care physician started her on pregabalin at 25 mg once daily at bedtime with the option to increase the dose by 25 mg weekly to a maximum of 50 mg/day. Following the combination therapy, the patient started to experience drowsiness, fatigue, dizziness, and even ataxia, which was deemed to cause by the therapeutic duplication. Upon discontinuation of pregabalin and dose titration of gabapentin (100 mg TID to 100 mg in the morning, 100 mg in the afternoon, and 200 mg at bedtime with the option to increase by 100 mg weekly to a maximum of 200 mg three times a day), the patient was successfully relieved of her fatigue, drowsiness, and dizziness. Her neuropathy symptoms also improved with the increased dose of gabapentin.
Study Author Conclusions	The authors highlight that there is no benefit of taking the gabapentinoids together because pregabalin has a six times higher affinity for binding to the α2δ subunit/gabapentin receptor and would have prevented gabapentin from binding. Concomitant use of both agents may increase renal burden as both agents undergo renal excretion, especially in patients with underlying renal dysfunction. The intention of this case report was to increase awareness about the adverse effects of these widespread medications. Gabapentin and pregabalin are being massively prescribed for neuropathic pain of all kinds of etiologies. However, if these medications are combined or if given in a high dose, they can lead to adverse effects such as dizziness, drowsiness, fatigue, weakness, and somnolence. These medications also carry the risk of addiction, which makes it even more important to control their prescribing.

References:
[1] Ghayur MN. Potential Adverse Consequences of Combination Therapy with Gabapentin and Pregabalin. Case Rep Med. 2021;2021:5559981. Published 2021 Jun 2. doi:10.1155/2021/5559981

Use of gabapentin and pregabalin for pruritus and neuropathic pain associated with major burn injury: A retrospective chart review
Design	Retrospective chart review N= 136
Objective	To explore and document the effect of gabapentin and pregabalin in children and adolescent burn survivors
Study Groups	Gabapentin only (n= 112) Gabapentin and pregabalin (n= 24)
Inclusion Criteria	Patients aged < 21 years with neuropathic pain associated with major burn injury previously failed diphenhydramine and hydroxyzine
Exclusion Criteria	Patients without complaint of pruritus
Methods	Patients were initially administered gabapentin for treatment. If symptoms were not alleviated, then pregabalin was added. This was due to the higher cost associated with pregabalin. Pruritus was measured via the Itch Assessment Scale Shriners. The smallest starting dose of gabapentin and pregabalin received was 50 mg TID. Patients were seen either weekly or biweekly to assess for dose adjustment. There were no known restrictions regarding other medications.
Duration	May 2011 to August 2015
Outcome Measures	Response to therapy, average effective dose for gabapentin and pregabalin
Baseline Characteristics		Gabapentin only (n= 112)	Gabapentin and pregabalin (n= 24)
Baseline Characteristics	Condition for treatment Pruritus only Pain only Pruritus and pain	98 2 12	6 0 18
Results	Endpoint	Gabapentin only (n= 112)	Gabapentin and pregabalin (n= 24)
	An adequate response to therapy based upon presenting condition Pruritus Neuropathic pain Pain and pruritus	91.4% 100% 43.3%	100% - 88.2%
	Maximum gabapentin failure dose for pruritus (leading to the addition of pregabalin), mg/kg/day Pruritus Pain and pruritus	32.8 ± 18.0 28.1 ± 18.3
		Age < 5 years (n= 82)	Age 6 to 12 years (n= 21)	Age > 12 years (n= 24)
	Gabapentin average effective dose, mg/kg/day	23.9 ± 10.3	27.0 ± 15.3	34.1 ± 15.7
	Pregabalin average effective dose, mg/kg/day	3.7	6.5 ± 3.5	4.7 ± 1.6
Adverse Events	Gabapentin: Hyperactivity in two patients. Sedation in one patient Gabapentin and pregabalin: nausea, vomiting, and headache in one patient which resolved when gabapentin was discontinued. Sedation in one patient
Study Author Conclusions	Gabapentin and pregabalin are effective in relieving pruritus and neuropathic pain in most burn survivors. In some instances, these medications can be given together. Few individuals reported side effects.
InpharmD Researcher Critique	There was limited information regarding baseline characteristics and the benefits of gabapentin and pregabalin treatment. The results were descriptive without a formal analysis. All responses to therapy were subjective, it may not be possible for some children to distinguish from pain and pruritus and benefits. Patients could have also been taking other medications such as antibiotics, benzodiazepines, and propanolol which could interfere with reported outcomes.

References:
[1] Kaul I, Amin A, Rosenberg M, Rosenberg L, Meyer WJ 3rd. Use of gabapentin and pregabalin for pruritus and neuropathic pain associated with major burn injury: A retrospective chart review. Burns. 2018;44(2):414-422. doi:10.1016/j.burns.2017.07.018