Neuropathic cancer pain: What we are dealing with? How to manage it?

Figures & data

Table 1 Terms used for classification of pain-related symptoms

Hyperalgesia	Attenuated pain response to a painful stimulus
Hypoalgesia	Diminished response to a painful stimulus
Allodynia	Pain that is associated with an unpainful stimulus (light touch, mild temperature)
Dysesthesia	An abnormal sensation that is developed by a normal stimulus

Table 2 Etiopathogenic disorders associated with neuropathic pain syndromes*

Toxicity	Chemotherapy, radiotherapy, arsenic/lead exposure, statin and isoniazid usage
Trauma	Phantom limb pain, postmastectomy pain, postthoracotomy pain, or any pain in major surgical regions
Compression	Nerve-entrapment syndromes like carpel tunnel syndrome, direct tumor compression, especially in tumor metastasis
Ischemia	Pain in diabetic food ulcers, vasculitis-associated neuropathy, Buerger’s disease
Infection	Postherpetic neuralgia, human immunodeficiency virus-associated neuropathy, herpes zoster-associated leprosy
Congenital diseases	Storage diseases, Fabry’s disease, amyloidosis
Autoimmune disorders	Chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, vasculitic neuropathy, and paraneoplastic syndromes like Eaton–Lambert syndrome, multiple sclerosis
Metabolic disorders	Diabetic neuropathy, uremic neuropathy, alcohol toxicity, beriberi

Note:

* Some of these mechanisms usually coexist in neuropathic pain syndromes.

Table 3 Acute cancer pain syndromes

Pain related to diagnostic approaches

• Biopsy (bx)-associated pain like bone marrow bx, transrectal prostate bx, or puncture-associated like lumbar puncture or arterial blood gas sampling, etc

• Paracentesis-associated pleurodesis; nephrostomy, biliary stent implantation, etc

• Pathologic fractures due to bony metastasis

• Intestinal/biliary/ureteric obstruction and/or perforation; visceral organ perforation like gastric or colonic tumor

Pain related to treatment (chemotherapy)

• Pain due to oral mucositis

• Acute polyneuropathy

• All-trans retinoic acid-induced bone pain

• Intrathecal chemotherapy induced headache (cerebrospinal fluid leakage or chemical meningitis)

• Fluoropyrimidine-induced angina

• Vasospasm (oxaliplatin)

• Steroid-induced perineal burning

• Painful hand–foot syndrome

• Locoregional chemotherapy pain

• Bone pain due to colony-stimulating factors

• Immunotherapy-associated myalgias (interferon)

• Analgesia-associated opioid-hyperalgesia syndrome or injection-side pain

Pain related to treatment (radiotherapy)

• Mucositis

• Early brachial plexopathy

• Radiation enteritis

• Acute myelopathy

Table 4 Chronic cancer pain syndromes

Pain related to tumor itself – somatic pain	Pain related to tumor itself – visceral pain	Neuropathic pain syndromes	Pain related to treatment – chemotherapy	Pain related to treatment – surgery	Pain related to treatment – radiotherapy
Tumor-related bone pain: directly due to metastasis itself or oncogenic hypophosphatemic osteomalacia	Peritoneal carcinomatosis Chronic intestinal obstruction	Leptomeningeal metastases Trigeminal neuralgia Glossopharyngeal neuralgia	Painful peripheral neuropathy Raynaud’s phenomenon Chronic glucocorticoid-treatment complications Compression fractures due to osteoporosis	Postmastectomy pain Postthoracotomy pain Phantom limb/breast pain Pain due to neck dissection Lymphedema pain	Late-onset brachial plexopathy Chronic radiation myelopathy Radiation enteritis Lymphedema pain Osteoradionecrosis
Tumor-related soft-tissue pain like pleural pain/ear pain/eye pain	Malignant perineal pain Ureteric obstruction	Lumbosacral radiculopathy/plexopathy Cervical radiculopathy
Paraneoplastic syndromes: hypertrophic osteoarthropathy, muscle cramps, Raynaud’s phenomenon		Brachial plexopathy Painful peripheral mononeuropathies Paraneoplastic sensory/motor/autonomic neuropathic pain

Table 5 Common neuropathic syndromes associated with cancer

Chemotherapy-induced neuropathy

Tumor invasion: leptomeningeal metastases

Neuralgias: trigeminal neuralgia or postherpetic neuropathy

Glossopharyngeal neuralgia

Radiculopathies and plexopathies: lumbosacral radiculopathy/plexopathy

Cervical radiculopathy/plexopathy

Brachial plexopathy

Painful peripheral mononeuropathies

Paraneoplastic sensory neuropathies

Horner’s syndrome

Enteric neuropathies

Eaton–Lambert myasthenic syndrome

Postsurgery neuropathies

Postradiotherapy neuropathies

Paraneoplastic motor neuropathy

Paraneoplastic visceral neuropathy

Table 6 Common chemotherapeutic agents involved in neuropathy process

Drug	Type	Onset, duration, recovery
Cisplatin	Chronic	1–6 months for onset
Carboplatin	Chronic	Years for recovery (more than 80%)
Oxaliplatin	Acute or chronic Cold-induced	Acute: even during infusion Chronic: same as cisplatin Years for recovery (more than 80%)
Taxanes	Chronic, rarely acute More with dose-dense taxane treatment	Onset within weeks 19% complete recovery 25% no recovery Paclitaxel-associated acute pain syndrome lasts 4–5 days
Vincristine	Subacute	Onset usually after 3 months
Vinblastine	Subacute	Recovery after 3 months of drug cessation
Bortezomib	Onset any time, mainly subacute or chronic	Dose reduction is recommended
Thalidomide	Dose-dependent	Recovery at 2 years or no recovery
Ixabepilone	Subacute or chronic	Onset is acute or subacute
Eribulin	Subacute or chronic	Quick recovery in mild cases Long-term data needed

Table 7 Adverse effects of opioids

Emesis	Bronchoconstriction
Constipation	Respiratory depression
Sedation	Delirium
Cough suppression	Seizures
Sedation	Noncardiogenic pulmonary edema
Pruritus	Immunodeficiency
Dry mouth	Allodynia

Table 8 Analgesic recommendations and warnings*

Drug group	Drug	Level of recommendation	Dose and titration	Common side effects	Precautions
Opioids	Morphine	First-line	10–30 mg po in opioid-naïve patients every 4 hours	Constipation, nausea, vomiting, pruritus, sedation, somnolence, micturition problems, dizziness, myoclonus	Respiratory arrest Opioid-induced hyperalgesia
	Oxycodone	First-line	5–15 mg po every 4–6 hours		Hepatic insufficiency
	Hydrocodone	First-line	2–4 mg every 3–4 hours		Renal insufficiency
	Transdermal fentanyl	First-line	12–25 μg every 72 hours, not recommended for opioid-naïve patients or acute pain		Methadone: high variability in half-life and pharmacodynamics; highest risk among opioids in terms of overdose, accumulation
	Methadone	Second-line/third-line	2.5–10 μg po every 4–8 hours
	Tramadol	Second-line	50–100 mg every 4–6 hours (IR) 100 mg once daily (ER)
	Codeine/acetaminophen	Second-line, not recommended in chronic cancer pain	30–60 mg po every 4–6 hours (according to codeine content)
	Tapentadol		50–100 mg every 6 hours (IR) 50 mg every 12 hours (ER)
Antidepressants – tricyclic	Nortriptyline	First-line	Start as 10–25 mg bedtime Usually effective as 50–150 mg Titration by 25 mg every 5–7 days	Dry mouth, constipation, dizziness, urinary retention Titration should be done no less than every few days	Cardiac disease Glaucoma
	Desipramine	First-line	Start as 10–25 mg at bedtime Usually effective as 50–150 mg at bedtime
	Amitriptyline	Second-line/third-line	Start as 10–25 mg at bedtime effective as 50–150 mg
Antidepressants – SNRIs	Duloxetine	First-line, effective in prevention of oxaliplatin-associated neuropathic pain	Start as 20–30 mg daily Usually effective in 60–120 mg daily doses	Nausea	Hepatic dysfunction Renal insufficiency
	Venlafaxine	First-line	225 mg twice daily, 37.5–75 mg daily increase after toleration	Nausea	Hepatic dysfunction Renal insufficiency
Antidepressants – norepinephrine–dopamine inhibitors	Bupropion	Third-line	Start as 75 mg twice daily Usually effective in 300–450 mg three times daily doses	Weight loss	Seizures
Antiepileptics – gabapentinoids	Gabapentin	First-line	Start as 100–300 mg twice daily Usually effective in 300–1,200 mg three times daily doses 2–3 step/week titration	Sedation, dizziness, edema
	Pregabalin	First-line	Start as 25–75 mg twice daily Usually effective in 150–300 mg three times daily doses 2–3 step/week titration	Sedation, dizziness, edema	Renal insufficiency
Topical antineuralgics	Topical lidocaine	First-line in cases with allodynia (level B)	1–3 patches daily 2 weeks	No systemic side effects Local irritation	None
	Topical capsaicin	Second-line/third-line	8% capsaicin, 1 patch dailyUsually effective – 3–4 patches daily	Local irritation	Application-related severe pain
Cannabinoids	Nabiximols	Third-line	Start as 0.5–1 mg once a day, titration maximum to 3 mg	Dizziness, somnolence, and dry mouth

Note:

* It should be kept in mind that most of the analgesic trials on pain were for nonmalignant pain syndromes.

Abbreviations: po, per os (by mouth); IR, immediate release; ER, extended release; SNRIs, serotonin-norepinephrine reuptake inhibitors.

Table 9 Nonpharmacological treatment approaches in neuropathic pain

Interventional approaches	Rehabilitative approaches	Psychological approaches	Neurostimulation	Integrative/alternative approaches
Neural blockade – neurolysis	Exercise	Cognitive behavioral therapy	Transcutaneous	Acupuncture/acupressure
Implant therapy – intrathecal drug delivery	Hydrotherapy	Relaxation therapy, guided imagery, other types of stress management	Transcranial	Massage
Injection therapies		Psychoeducational interventions	Implanted
Radiotherapy-ablation therapies