antidepressants for neuropathic pain (antidepressant therapy for neuropathic pain)

Last edited 05/2023 and last reviewed 05/2023

Antidepressants and Neuropathic Pain

Mechanism of action of antidepressants in neuropathic pain (1):

• unknown
• multiple mechanisms are likely to be involved
• one theory is that antidepressants exert their effects on serotonin and norepinephrine, particularly along the descending spinal pain pathways
• may also exert adjunctive therapeutic influences through histamine receptors as well as modulation of sodium channels

Many antidepressants are effective in the treatment of pain, but not all and not to the same degree.

A review states the pharmaceutical therapies for neuropathic pain are (2):

• first-line treatments
  • tricyclic antidepressants (TCA; e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (SNRIs; i.e., duloxetine and venlafaxine), and gabapentinoids (i.e., gabapentin and pregabalin)
    
    
• second-line treatments
  • weak opioid analgesics (e.g., tramadol and tapentadol) are recommended
  • topical agents (i.e., lidocaine plaster and capsaicin patch) are recommended as second-line pharmacological treatments exclusively in peripheral neuropathic pain
    
    
• third-line treatments
  • strong opioids (e.g., morphine and oxycodone) are recommended both in central and peripheral neuropathic pain conditions, whereas botulinum toxin type A-haemagglutinin complex (BoNTA) can be recommended only in peripheral neuropathic pain conditions
    
    
• trigeminal neuralgia
  • carbamazepine (CBZ) and oxcarbazepine (OXC) are the first-choice drugs
  • CBZ (200-400 mg/day) and OXC (300-600 mg/day) are recommended options for TN (2)

In this review there is a categorization of neuropathic pain as either peripheral neuropathic pain or central neuropathic pain (2):

• subtypes of chronic peripheral neuropathic pain are the following:
  • trigeminal neuralgia (TN)
  • chronic NP after peripheral nerve injury
  • painful polyneuropathy
  • postherpetic neuralgia
  • and painful radiculopathy
• chronic central neuropathic pain:
  • chronic central NP associated with spinal cord injury (SCI),
  • chronic central NP associated with brain injury,
  • chronic central poststroke pain,
  • and chronic central NP associated with multiple sclerosis (MS)

Tricyclic antidepressants

• the most studied antidepressants for the treatment of neuropathic pain
• inhibit the reuptake of serotonin and norepinephrine at the synapse, but do so differentially according to chemical structure
  • tertiary amines (e.g., amitriptyline, doxepin, imipramine) inhibit serotonin to a greater degree than norepinephrine
  • secondary amines (e.g., desipramine, nortriptyline) have more pronounced effects on norepinephrine
  • stated that tertiary amines are somewhat more effective than the secondary amines (1)
  • pain relief appears to be independent of the antidepressant effects of these drugs and may be achieved at doses lower than those used in the treatment of depression
  • amitriptyline (10-150 mg/day) is recommended as a first-line drug in the treatment of all neuropathic pain conditions with strong recommendation based on moderate quality of evidence (2)
  • TCAs though are associated with risk of significant adverse effects (e.g., weight gain, anticholinergic effects, orthostatic hypotension, cardiovascular effects, lethality in overdose)

Selective serotonin reuptake inhibitors

• selective serotonin reuptake inhibitors (SSRIs) exert their efficacy predominantly through the reuptake inhibition of serotonin
• data with regard to SSRIs is more inconsistent in comparison to TCAs in this area of application
• paroxetine and citalopram have demonstrated modest efficacy in the management of neuropathic pain, whereas fluoxetine has not demonstrated any efficacy (1)
• overall impression is that SSRIs are less effective than other antidepressant options in the treatment of neuropathic pain

Venlafaxine

• mixed-action antidepressant that predominantly inhibits serotonin reuptake at low doses and norepinephrine reuptake at higher doses
• unlike SSRIs and like TCAs, venlafaxine affects both of the key neurotransmitters that are hypothesized to be involved in the modulation of neuropathic pain
• study evidence that venlafaxine is effective for the management of neuropathic pain at doses of 150mg per day or higher (i.e., typical antidepressant doses)
• in the treatment of neuropathic pain, venlafaxine is comparable to imipramine, suggesting that it may be comparable to other TCAs as well (1)

Bupropion

• inhibits the reuptake of norepinephrine and dopamine
• bupropion SR has evidence of similar in efficacy to TCAs

Duloxetine

• duloxetine is an antidepressant approved by the US Food and Drug Administration for the treatment of neuropathic pain
  • purportedly a dual-action drug (i.e., it inhibits both serotonin and norepinephrine)
  • evidence that is an effective agent in the treatment of neuropathic pain
  • doses for the treatment of neuropathic pain as well as depression are between 60mg and 120mg per day

Serotonin-norepinephrine reuptake inhibitors (SNRIs; i.e., duloxetine and venlafaxine)

• duloxetine and venlafaxine are categorized as SNRIs. These medications inhibit both serotonin and norepinephrine (both are theorized to have a role in the development of pain via spinal pain pathways) (1,2)
• from the SNRI group, venlafaxine (150-225 mg/day once a day) and duloxetine (60-120 mg/day once a day) are the first-choice drugs with strong recommendation based on high quality of evidence for all NP conditions (2)

A review concluded that (1):

• "..current diversity of available antidepressant options, many different types appear to be efficacious in the treatment of pain, with the exception of SSRIs."

Further reviews suggest:

• first-line treatments (1)
  • tricyclic antidepressants (TCA; e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (SNRIs; i.e., duloxetine and venlafaxine), and gabapentinoids (i.e., gabapentin and pregabalin)
• a Cochrane review states "..the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose.." (3)

Reference:

1. Sansone RA, Sansone LA.Pain, Pain, Go Away - Antidepressants and Pain Management. Psychiatry (Edgmont). 2008 Dec; 5(12): 16-19.
2. Szok D et al. Therapeutic Approaches for Peripheral and Central Neuropathic Pain. Behav Neurol.2019 Nov 21;2019:8685954. doi: 10.1155/2019/8685954. eCollection 2019.
3. Birkinshaw H, Friedrich CM, Cole P, Eccleston C, Serfaty M, Stewart G, White S, Moore RA, Phillippo D, Pincus T. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database of Systematic Reviews 2023, Issue 5. Art. No.: CD014682. DOI: 10.1002/14651858.CD014682.pub2. Accessed 12 May 2023.