Which is Better for Pain: Gabapentin or Amitriptyline?

Pain is a distressing sensory and emotional experience that can negatively affect a person's quality of life, overall health, psychological well-being, and social and economic well-being. It is often described as burning, stabbing, or shooting. Pain can also be associated with a disease, for example peripheral neuropathy, postherpetic neuralgia, or migraine pain, and can be described in terms of duration like acute or chronic.

There are several classes of medications used to relieve different kinds of pain. They range from over-the- counter medicines (OTC), for treating headache and toothache, to eclectic (often off-label medications) like carbamazepine, gabapentin, and amitriptyline. 

Nociceptive vs. Neuropathic Pain

Technically speaking, pain can be grouped into neuropathic pain and nociceptive pain (non-neuropathic). Neuropathic pain is described as "pain induced by a somatosensory nervous system injury or disease." Neuropathic pain results when there is damage to a single nerve or nerve bundle, either because of inflammation and irritation or direct compression of the neural tissue.  

On the other hand, nociceptive pain is felt when the nerve endings lining different parts of the body react to painful stimuli rather than a result of direct injury to the nerve. Think about the last time you had a pinprick or muscle ache. Usually, the pain subsides as soon as the irritant is removed. However, this is not often the case with neuropathic pain, which can persist even though the injury is repaired. Neuropathic pain is often chronic in nature, and treating it is not as straightforward as nociceptive pain. 

What is Amitriptyline?

Although versatile in terms of therapeutic uses (ranging from treatment of stubborn migraines to bed-wetting in children), the main indication of amitriptyline is in the treatment of depression. It is classed as a tricyclic antidepressant drug that has been around for a long time, and is prescribed for pain rather than depression.

Most clinicians consider amitriptyline as the first treatment option for neuropathic pain (amitriptyline is commonly used to treat persistent neuropathic pain, such as fibromyalgia) as there is more clinical evidence that shows it works well. Amitriptyline also has other benefits: it can help you sleep, and also treats chronic tension headaches and migraines. The optimal amitriptyline dosage for pain management is uncertain, although the dose for pain management ranges from 10-75 mg daily. Amitriptyline, unlike other pain medications, does not function immediately.

How does Amitriptyline Work against Pain?

It works by disrupting the reuptake of neurotransmitters like serotonin and noradrenaline that signal pain at the nerve terminals. Ion-channel blocking effects on sodium, potassium, and NMDA channels at the central and spinal levels are also part of the mechanism of action. The actions of noradrenaline, sodium, and NMDA are known to be implicated in neuropathic pain maintenance and migraine prophylaxis. Amitriptyline's pain-relieving qualities are unrelated to its anti-depressive characteristics.

Side effects of Amitriptyline

The common side effects of amitriptyline include the following: 

  • Weight gain
  • Reduced appetite (in some cases) 
  • Constipation 
  • Withdrawal symptoms (risk of addiction)
  • Drowsiness
  • Urinary difficulties
  • Disturbances in cardiac rhythm 
  • Dry mouth
  • restlessness/aggression
  • Nausea 
  • Nasal congestion 

What is Gabapentin?

The drug belongs to a class of  anticonvulsants in which pregabalin belongs (gabapentinoids). Besides treating some forms of seizures, gabapentin is often used to treat postherpetic neuralgia and peripheral neuropathic pain - other interesting indications are hot flashes, and restless leg syndrome.

The drug which is also known as Neurontin has been shown to be efficacious and to have manageable side effects in randomized controlled trials. Higher doses are prescribed for neuropathic pain (unlike those for epilepsy), usually ranging between 300-3600 mg per day. 

How does Gabapentin Work Against Pain?

The mechanism of action is not clear, but it is known to interact with a unique subunit of GABA receptors to interfere with pain transmission. 

Side effects

The side effects of gabapentin include:

  • Withdrawal  symptoms when discontinued abruptly (risk of addiction)
  • Sleeping problems 
  • Loss of appetite 
  • Confusion 
  • Visual disturbances 
  • Constipation 
  • Elevated liver function tests 

Can you take Amitriptyline and Gabapentin together?

Given that neuropathic pain (and other forms of pain like cancer pain and migraine pain) is difficult to treat, physicians have explored combination therapy, which has shown better efficacy compared to single treatment modalities (Serrano). Another drug is added if partial but insufficient pain relief is achieved, as combination therapy may be more successful than single-drug therapy. Ideally, medications complementary to each other (with different mechanisms of action) are prescribed for synergy and to avoid addictive side effects. It is important to note that the doses of the individual medicines in the combination are usually reduced. 

Combinations such as gabapentin/pregabalin and duloxetine (or other tricyclic antidepressants) are often tried for pain management.1 The prescribing decision is best left to highly trained specialists and consultants who weigh the benefits versus the risk. The benefits of combination therapy include greater pain reduction and lower side effects from each drug in the combination (since their doses are lower). 

Interactions

Drug-drug interactions are observed with combination therapies. Combinations of amitriptyline with certain medications like Monoamine Oxidase Inhibitors (moclobemide and selegiline) and buprenorphine can lead to serotonin syndrome (high blood pressure, confusion, agitation, cardiac disturbances etc.) which can be fatal. Due to potentially harmful interaction, combination with OTC nasal decongestants, anticholinergic drugs, and adrenergic drugs is also discouraged. 

Unlike amitriptyline, the potentially dangerous drug interactions are fewer with gabapentin. This doesn't mean gabapentin doesn't interact with other medicines like antacids or contraceptives. Cases of respiratory depression have been reported for the combination of gabapentin and opioid medicines, eliciting caution among prescribers. 

Which Drug is better?

It depends on preference, as both have pros and cons. Both gabapentin and amitriptyline are good nerve pain relievers. Amitriptyline can be better for some patients because of the convenient dosing schedule. On the other hand, most patients prefer gabapentin (the relatively newer medication) over amitriptyline due to less anticholinergic effects (dry mouth, constipation) and less sedation. In fact, adverse effects seem to be more common with amitriptyline than gabapentin. For patients with heart, liver, or kidney problems, gabapentin is a better choice than amitriptyline.

Clinically significant variations in efficacy (as measured by the Daily Pain Diary Score or Overall Pain Relief Score) between the two treatments are yet to be established from scientific studies. Going by head-to-head clinical trials, there is no glaring evidence that one drug is superior to the other.2 A randomized, open-label, parallel group study showed that gabapentin was safer and more effective than amitriptyline in patients with painful diabetic peripheral neuropathy. According to Keskinbora and colleagues, gabapentin was more effective (especially for sudden shooting pain) and better tolerated compared to amitriptyline.3

Conversely, the tricyclic antidepressant amitriptyline (Elavil) has been linked to considerable analgesia in a variety of animal models; it has long been the medicine of choice for pain management in individuals with pain due to spinal cord injuries. Furthermore, it has been demonstrated in studies to be the most effective treatment for nerve pain caused by diabetes, herpes zoster, and fibromyalgia, a painful muscular illness.

Are different drugs better depending on the type of pain?

There are other medications that are just as safe and effective as gabapentin and amitriptyline. They include duloxetine (serotonin norepinephrine reuptake inhibitor SNRI), pregabalin and carbamazepine, which are effective for migraines and neuropathic pain; tramadol, morphine, and non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or diclofenac can be prescribed for nociceptive pain and musculoskeletal pain.4    

Conclusion

Both gabapentin and amitriptyline are important prescription medications that have a wide range of therapeutic uses, including pain management. They are routinely prescribed for neuropathic or nerve-related pain. Despite the fact that both have shown some success in the treatment of chronic pain, both are prescribed with caution due to the potential for addiction and other side effects. Both medications affect the neurological system, but their precise modes of action are uncertain. The choice of either agent boils down to patient and clinician preference, even though both medications have their pros and cons. Ultimately, there is no evidence to suggest that one is superior to the other. 

References 

  1. Serrano Afonso A, Carnaval T, Videla Cés S. Combination Therapy for Neuropathic Pain: A Review of Recent Evidence. J Clin Med. 2021 Aug 11;10(16):3533. doi: 10.3390/jcm10163533. PMID: 34441829; PMCID: PMC8396869
  2. Sekar P, Punnagai K, David DC. Comparative Study of Safety and Efficacy of Gabapentin Versus Amitriptyline in Patients With Painful Diabetic Peripheral Neuropathy, A Randomized open Label Parallel Group Study. Biomedical and Pharmacology Journal. 2017 Sep 25;10(3):1259–65.. PMID: 30318260
  3. Keskinbora K, Pekel AF, Aydinli I. Periferik nöropatik ağrinin kontrolünde gabapentin ve amitriptilinin etkinliğinin karşilaştirilmasi [Comparison of efficacy of gabapentin and amitriptyline in the management of peripheral neuropathic pain]. Agri. 2006 Apr;18(2):34-40. Turkish. PMID: 17089234.
  4.  Attal N. Pharmacological treatments of neuropathic pain: The latest recommendations. Rev Neurol (Paris). 2019 Jan-Feb;175(1-2):46-50. doi: 10.1016/j.neurol.2018.08.005. Epub 2018 Oct 11

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Ezekwesiri Nwanosike

Master's degree - Drug Discovery and Business Strategy, The University of Huddersfield
I am a business-minded Pharmacist who specializes in leveraging clinical data to improve patient wellbeing. My passion is ensuring that quality, safe and effective health information/products are within the reach of everyone.

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