Table 2.
Overview of therapy recommendations for treatment of CIPN by leading guidelines of expert societies. Please note the approval status of respective drugs (status: October 2020)
| Therapeutic procedure to treat CIPN Approval for pain treatment in EU/USA |
Mode of action | Comments and frequent side effects | Recommendations of expert society | References | ||
|---|---|---|---|---|---|---|
| S3 Guideline Supportive Therapy (DKG/ASORS, DGHO, DEGRO) 2017 [6] | ASCO Practice Guideline 2014 [7] | German Society for Neurology (DGN) 2019 [44] | ||||
| SSNRI | ||||||
|
Duloxetine EU: approved for painful diabetic peripheral neuropathy USA: approved for diabetic peripheral neuropathic pain |
• Analgesic properties due to presynaptic reuptake inhibition of serotonin and noradrenaline • Increased activation of inhibitory system of descending nerves (pain inhibition) |
• Nausea, dry mouth, somnolence, headache, anxiety | + | + | + |
Smith et al. [45]; Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 Schlereth et al. [44] |
|
Venlafaxine EU/USA: off-label |
• Analgesic properties due to presynaptic reuptake inhibition of serotonin and noradrenaline • Increased activation of inhibitory system of descending nerves (pain inhibition) |
• Nausea, dry mouth, somnolence, headache, anxiety, hypertension | n.s. | (+) |
Durand et al. [46] Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 Schlereth et al. [44] |
|
| Tricyclic antidepressants | ||||||
|
Amitriptyline, nortriptyline EU: Amitriptyline: approved for neuropathic pain, nortriptyline: off-label USA: off-label |
• Blocking of voltage-dependent sodium channels • Presynaptic reuptake inhibition of biogenic amines (e.g., noradrenaline, serotonin) |
• Drowsiness, fatigue, dizziness, hypotension, weight gain | (+) | - | + |
Kautio et al. [47] Hammack et al. [48] Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 Schlereth et al. [44] |
| Anticonvulsants | ||||||
|
Calcium channel modulator: Gabapentin—EU: approved for peripheral neuropathic pain, USA: approved for postherpetic neuralgia Pregabalin—EU: approved for peripheral and central neuropathic pain, USA: approved for diabetic peripheral neuropathic pain; postherpetic neuralgia; neuropathic pain associated with spinal cord injury |
• Bind to voltage-gated calcium channels on nociceptive neurons in PNS and CNS with high affinity • Reduce activating calcium influx on peripheral/central neurons |
• Gabapentin: somnolence, dizziness • Pregabalin: drowsiness, somnolence, peripheral edema, weight gain • Administration of gabapentin is frequently associated with vertigo and should be considered with care in case of certain functional impairments (e.g., gait disorder). |
(+) | - | + |
Mishra et al. [49] Rao et al. [50] Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 |
|
Sodium channel modulator: Carbamazepine EU: approved for trigeminal neuralgia and diabetic peripheral neuropathic pain, USA: approved for trigeminal neuralgia |
• Stabilizes membranes at voltage-gated sodium channels on sensitized nociceptive neurons in PNS and CNS • Reduces spontaneous activity of these neurons |
• Unfavorable side effect profile • Particularly, hyponatremia as well as drug interactions should be considered |
- | - | - |
Mishra et al. [49] Rao et al. [50] Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 |
| Opioids and cannabinoids | ||||||
|
Opioids (e.g., tramadol, oxycodone, tapentadol) EU/USA: approved for moderate-to-severe pain |
• Agonist effects at μ-opioid receptor in the CNS • Dependent on intrinsic activity at the receptor: segregation into low-potent (weak) and high-potent (strong) opioids • Some also act via noradrenergic and serotonergic reuptake inhibition on the inhibitory system of descending nerves (pain inhibition) |
• Sedation, dizziness, headache, constipation, nausea, itch • Dependency, abuse |
(+) | n.s. | (+) |
Finnerup et al. [51] Nagashima et al. [52] Sommer et al. Eur J Pain, 2020. 24(1):3-18 Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 Schlereth et al. [44] |
|
Cannabinoids EU/USA: off-label |
• Agonists at CB1 receptors in CNS, spinal cord, and peripheral nerves • Act via inhibition of neuronal excitability |
• Some cannabinoid compounds are psychoactive • Synthetic cannabinoid receptor agonists may have higher psychosis-inducing potential than natural cannabis and should be considered with care |
n.s. | n.s. | - |
van Amsterdam et al. J Psychopharmacol, 2015. 29(3):254-63 Schlereth et al. [44] |
| Topical therapies | ||||||
|
Lidocaine patch (700 mg) EU/USA: approved for postherpetic neuralgia |
• Inhibits ectopic action potentials via blocking of abnormally functioning (sensitized) Nav1.7 and Nav1.8 sodium channels in the dermal nociceptors • May have anti-inflammatory properties via regulation of T cell activity and suppression of nitric oxide production • Act as a mechanical barrier to the area of allodynia, preventing stimulation |
• Burning, erythema, pruritus, or skin irritations at application site • Unlike conventional lidocaine patches, lidocaine patches developed for pain relief do not cause cutaneous hypoesthesia |
(+) | n.s. | (+) | Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 |
|
Capsaicin patch, 179 mg (EU)/8% (US) EU: approved for topical treatment of peripheral neuropathic pain as monotherapy or in combination with other pharmaceutical products for the treatment of pain USA: approved for postherpetic neuralgia and diabetic peripheral neuropathic pain |
• Highly selective agonist of TRPV1 that induces activation of TRPV1-expressing cutaneous nociceptors • Initial TRPV1 activation results in transient ion influx (Na+, Ca+) with subsequent nerve depolarization and propagation of action potentials • Prolonged capsaicin exposure induces reversible defunctionalization of nociceptor function, thereby providing pain relief for an extended period |
• Pain or erythema as well as burning sensation at application site • Adverse reactions are usually transient, self-limiting, and mild-to-moderate in intensity |
(+) | (+)# |
+ (In case of localized neuropathic pain, the capsaicin patch should be considered for first-line therapy) |
Filipczak-Bryniarska et al. [53] Maihöfner and Heskamp [54] van Nooten et al. [55] Binder and Baron Dtsch Arztebl Int, 2016. 113(37):616-625 Vinik et al. BMC Neurol, 2016. 16(1):251 Anand and Bley [56] |
| Gel formulation (baclofen, amitriptyline and ketamine or amitriptyline and ketamine) | • Combined mode of action, i.e., GABAergic modulation, blockade of sodium channels and glutamatergic (NMDA) receptors | Not specified | - | - | n.s. |
Barton et al. [57] Gewandter et al. [58] |
| Cream formulation (1% menthol) | • Selectively activates TRPM8, which is also activated upon sensation of cold temperature and after sensory nerve injury | Not specified | (+) | - | n.s. |
Hershman et al. [7] Fallon et al. [59] |
+, recommended for treatment of CIPN by indicated guideline; -, not recommended for treatment of CIPN by indicated guideline; brackets indicate weak recommendation, e.g., due to low-quality medical evidence for CIPN and/or unfavorable side effect profile; n.s., not specified; SSNRI, selective serotonin-noradrenalin reuptake inhibitor; CNS, central nervous system; GABA, gamma-aminobutyric acid; NMDA, glutamatergic N-methyl-d-aspartate; PNS, peripheral nervous system; TRPV1, transient receptor potential vanilloid 1; TRPM8, transient receptor potential melastatin 8
#CIPN-data were not yet available at publication date