Gabapentin/Pregabalin

Question 1

What is the primary mechanism of action of gabapentin and pregabalin?

Answer 1

presynaptic inhibition of the alpha-2-delta-1 subunit of voltage-gated calcium channels –> decreases presynaptic calcium influx –> decreased release of excitatory neurotransmitters from the presynaptic membrane.

Question 2

What is the difference between gabapentin and pregabalin?

Answer 2

Pregabalin has increased binding affinity at the alpha-2-delta-1 subunit –> potentially more potent analgesic

Question 3

Name 6 indications for pregabalin in humans?

Answer 3

• prevention of partial onset seizures
• pain from fibromyalgia
• diabetic nerve pain
• pain associated with diabetic peripheral neuropathy
• spinal cord injury nerve pain
• post-herpetic neuralgia

Question 4

Name 4 indications for usage of gabapentin?

Answer 4

• seizures (humans as sole agent + as multimodal approach in dogs/cats)
• pain from post-herpetic neuralgia (humans)
• neuropathic pain (humans)
• chronic pain
• osteoarthritis (possible neuropathic component)
• anxiolysis (anxiety can exacerbate the level of pain experi- enced by the patient in people)

Question 5

Discuss why early implementation of gabapentin therapy in the critically ill patient may be beneficial?

Answer 5

• decrease the development of chronic pain
• primarily neuropathic
• maladaptive pain

Question 6

Disuss evidence of gabapentin causing anxiolysis in cats and dogs?

Answer 6

Cats:
Gabapentin was shown to reduce fear responses in trapped cats

Dogs:
No evidence, but usage as anxiolytic has been reported in ICU dogs

Question 7

Name 3 types of pain for which gabapentin has been documented to be useful in people?

Answer 7

• burns
• neurologic injury
• visceral pain,

Question 8

Discuss evidence of gabapentin as an analgesic drug in dogs?

Answer 8

1. Dogs undergoing mastectomy receiving NSAIDs plus gabapentin required fewer opioid rescue doses than dogs receiving NSAIDs alone
2. Dogs that have undergone surgery for herniated disc extrusion had no significant pain relief with gabapentin compared with placebo
3. Plessas et al. in Vet Rec 2015: Comparison of gabapentin versus topiramate on clinically affected dogs with Chiari-like malformation and syringomyelia:
   no differences in pain scores in dogs with syringomyelia receiving gabapentin, but gabapentin-treated dogs had improved QoL scores

• gabapentin has been reported to decrease both anxiety and visceral pain in research rats
• early initiation of analgesic therapy with drugs such as gabapentin could predictively decrease the development of chronic neuropathic pain in animals

Question 9

Discuss evidence of pregabalin as an analgesic drug in dogs?

Answer 9

Postoperative pain was lower in dogs receiving perioperative pregabalin plus opioids than opioids alone following surgery for intervertebral disc herniation

Question 10

Discuss evidence of gabapentin as an analgesic drug in cats?

Answer 10

two case reports supporting gabapentin use in cats with chronic pain from trauma:

1. Lorenz et al. in JFMS 2013: Long-term use of gabapentin for musculoskeletal disease and trauma in three cats
2. Vettorato E, Corletto F in VAA 2011: Gabapentin as part of multi-modal analgesia in two cats suffering multiple injuries

Question 11

Discuss the recommendation mentionend in SACCM 3 for use of gabapentin in ICU and the rational behind it?

Answer 11

“Gabapentin administration should be considered for any patient in the ICU with preexisting neuropathic pain, regardless of whether or not the pain source is related to the reason for the hospitalization, unless contraindications are present”

Rational:
- drug with high margin of safety
- potential to prevent/treat neuropathic pain

Question 12

What is the primary gabapentin-mediated side effect?

Answer 12

sedation

= more common in patients receiving high gabapentin dos- ages and/or receiving other sedative drugs like opioids

Question 13

Name 6 possible side effects of gabapentin?

Answer 13

1. sedation
2. ataxia
3. weakness
4. diarrhoea
5. inappetence
6. agitation (rare)
7. profound respiratory depression reported in humans when used in conjuction with opioids –> hat not been reported in dogs/cats but should be considered

Question 14

Profound respiratory depression is a side effect of gabapentin use in people, when used in conjunction with opioids. Why is this side effect less likely to occur in dogs/cats?

Answer 14

veterinary patients experience less opioid-induced hypoventilation than humans

Question 15

At what dosage of pregabalin has sedation in cats been described?

Answer 15

reported after a single oral pregabalin dose of 4 mg/kg

Question 16

How is oral gabapentin absorbed in the body? What pharmacokinetic profile does oral gabapentin have? How does this impact bioavailability?

Answer 16

• via an L-amino acid transport system
• the transport system is saturable –>disproportionate nonlinear pharmacokinetics –> gabapentin serum concentration that does not increase linearly with the drug dose
• bioavailability of gabapentin decreases from 60% to 33% as dosage increases from 900 to 3600 mg/day in people

This disproportionate pharmacokinetics may also occur in dogs (Kukanich B, Cohen RL in Vet J 2011: Pharmacokinetics of oral gabapentin in greyhound dogs)

Question 17

How often must gabapentin be administered in dogs/cats to provide analgesic serum concentrations?

Answer 17

q6-8hr

Question 17

How do gabapentin and pregabalin defer in regard to their pharmacokinetic profile?

Answer 17

Pregabalin does not depend on a transport system for absorption and pharmacokinetics are linear (first order) in humans and presumed linear in dogs and cats.

Question 18

How is gabapentin metabolised in people and dogs/cats?

Answer 18

People + cats (suspected): primarily renal
Dogs: renal but also requires hepatic metabolism

Question 19

How does renal disease affect gabapentin dosage regime in dogs and cats and why?

Answer 19

Due to renal excretion gabapentin may undergo more rapid accumulation, and thus more rapid onset of adverse effects, in cats and dogs with renal disease and dogs with hepatic disease.

• lower starting dose and slower dose escalation are recommended

Question 20

How does hepatic disease affect gabapentin dosage regime in dogs and cats and why?

Answer 20

Dogs:
Due to hepatic metabolisation gabapentin may undergo more rapid accumulation, and thus more rapid onset of adverse effects
- lower starting dose and slower dose escalation are recommended

Cats:
seem to be have primary renal excretion only, so are not affected.

Question 21

How is pregabalin excreted in people and dogs/cats?

Answer 21

primarily renal (suspected in dogs/cats)

Question 22

What are the recommended dosages for gabapentin in dogs/cats?

Answer 22

Anxiolysis:
10–20 mg/kg q8-12h
dosages up to 60 mg/kg as one-time prestressor administration are anecdotally described.

Acute or chronic pain:
10–20 (up to 40–50) mg/kg q8h

Renal insufficiency:
- starting dose of 5 mg/kg q12h

Question 23

What are the recommended dosages for pregabalin in dogs/cats?

Answer 23

very little data; single dose research studies:

Dogs:
- starting dose of 4 mg/ kg q12h

Cats:
- 1–2 mg/kg q12h