Chemotherapy induced peripheral neuropathy (CIPN)

Chemotherapy induced peripheral neuropathy (CIPN) is a potential side effect in any patients receiving neurotoxic chemotherapy, it has sensory, motor and autonomic components and can be:

• Acute i.e. during chemotherapy cycles, often maximal at the time of the infusion
• Chronic i.e. persistent after 3 months post last chemotherapy. 

Acute CIPN has a predominance of sensory components with patients often complaining of intensely unpleasant sensations rather than pain and it can be misleading if the clinician only asks about pain. In acute CIPN we can see associated joint pains thought to be due to neurotoxicity affecting the synovial lining of joints.

Chronic CIPN can be predominantly sensory, or any mixture of sensory, motor and autonomic. Chronic CIPN is defined as lasting for at least 3 months post chemotherapy.  Not all acute CIPN goes on to chronic CIPN and similarly not all chronic CIPN is preceded by acute CIPN.  After completion of chemotherapy, existing CIPN can go through a period of deterioration over 3-4 months which is known as coasting.  At the 3-4 month period there is usually a stabilisation and in roughly 50% of patients a gradual improvement over a year.  The remaining 50% will have some level of unacceptable CIPN a year after finishing chemotherapy.  Our systematic review¹ and meta-regression suggests a high overall prevalence of CIPN, maximum within the first month after treatment, and falling over time. Overall, approximately one-third of patients (higher in paclitaxel) can expect to have chronic CIPN 6 months or more after the end of chemotherapy.

Generally, the longer the duration of poorly controlled CIPN the more challenging management becomes. There are no known preventative treatments for CIPN, however early identification of CIPN, particularly after the first cycle helps to identify susceptible patients who may go on to have challenging CIPN and clinical reassessment of chemotherapy dosing is important.

Reported clinical risk factors for CIPN include:

• Baseline neuropathy e.g. diabetes
• History of excessive alcohol intake
• Decreased creatinine clearance
• Specific sensory changes during chemotherapy treatment including:
  • Cold allodynia (pain in response to a non-painful cold stimulus) and
  • Cold hyperalgesia (exaggerated pain in response to a painful cold stimulus, such as winter temperatures and very cold water).

Onset of these cold sensitivities after just one cycle of chemotherapy is a red flag and such patients should have both a chemotherapy dose review and proactive management of CIPN - see below.

In general, the earlier the identification and management of CIPN, the higher the likelihood of preventing chronic severe CIPN. The best way to manage both acute and chronic CIPN is by taking a systematic approach starting with simple non-systemic treatments with no known toxicities and working up to systemic treatments if simpler treatments do not work.

The most detailed and accurate assessment can be carried out by using the EORTC CIPN-20 questionnaire which provides more information than the Common Toxicity Criteria (CTCAE). In patients with early onset of CIPN and the worrying sign of cold sensitivity, the CIPN 20 will provide a more accurate initial and ongoing assessment of CIPN.

In the average patient the common complaints will be of:

• progressive unpleasant sensations, only sometimes described as pain, particularly in the feet as the day goes on;
• burning in the feet especially at night, feet feeling like blocks of ice while not cold to the touch, tingling
• pins and needles;
• numbness (unpleasant sensations and pain can occur in numb areas).

The hands have a very similar profile but often less severe than the feet.

Occasionally in severe CIPN, the patient will complain of muscle spasm and in very severe cases this can travel high in the legs mimicking muscle cramp and even referred neuropathic pain. Shoes can be difficult to tolerate. Cold weather usually exacerbates CIPN, and warm weather helps.

On examination there can be negative signs (nil to find or just painless numbness) or positive signs where classically there is sensitivity to light touch with cotton wool, there can be sensitivity to temperature, particularly cold, and this can be elicited by a touching with a simple alcohol swab when the cold may be exaggerated and even painful. Occasionally cold is not felt at all or felt as warm. Abnormal signs can occur within a numb area.

The hierarchy of treatment approaches is as follows and all apply to concomitant joint pains:

1. Physiotherapy for small fibre neuropathy.^2-5 Occupational therapists and podiatrists can also play an important role in helping people managing the consequences of peripheral neuropathy.
2. Peripheral neuropathy socks either ankle or knee length depending on the degree of neuropathy and what the patient finds more comfortable
3. Menthol 5% in aqueous cream used twice daily; lower strengths may be ineffective and strengths in excess of 5% should not be used as can worsen pain. Allow 40 mins for drying of menthol in am before putting on socks.^6,7  
   Edinburgh guidance on the application of menthol in aqueous cream

Points 1, 2 and 3 can be introduced simultaneously without specialist input as a simple multimodality approach at first identification

4. Topical ^†lidocaine 5% plasters can be considered
   • Topical ^†lidocaine 5% patches, usually start with 1.5 per foot overnight, putting in place in early evening or morning, depending on period of maximum discomfort, usually on sole of foot and over toes.
5. TENS with conductive gloves and socks  Trial in patients who find rubbing the hands and feet helpful. 
   • TENS machines may be accessed through local supportive care, pain clinic or palliative care service. Conductive gloves and socks can be purchased online.

Introduce 4 or 5 initially on top of 1-3, eliminating anything which does not help or is unacceptable with reassessment

1. Systemic pharmacological approach should start with duloxetine 30 mg orally in the as a starting dose. It can cause wakefulness at night, therefore prescribe in the morning.⁸  
2. Tricyclic antidepressants such as ^†amitriptyline or ^†imipramine (which has fewer sedative side effects) can be used; the anticonvulsants ^†pregabalin and ^†gabapentin can also be considered, however there is no evidence base for these drugs. It may be that a drug is chosen to treat more than one symptom e.g. to aid sleep, anxiety, menopausal symptoms, post breast surgery pain or joint pain.
3. ^†Capsaicin cream. In some cases of severe ongoing CIPN, high dose capsaicin patch 8% can be considered.  This is applied as a one-off treatment in a chronic pain clinic and this can be preceded by a trial of topical capsaicin cream 0.05%, however, lack of response to capsaicin cream does not predict response to high dose capsaicin patch. High dose capsaicin patch only indicated in chronic CIPN.
4. Opioids should be avoided except in cases where there is no response to any of the above, where a trial of low dose opioid could be considered.
5. Patients unresponsive to the standard approaches above can have a trial of acupuncture if accessible locally.⁹

• Bowel: autonomic neuropathy will often lead to constipation and a general alteration of bowel habit which can be challenging.
• Postural hypotension is another well identified autonomic problem, which can be overlooked, as falls are often put down to motor problems.
• General care with well-fitting comfortable shoes, trying to stay warm in cold temperatures, and being aware that hot and cold water may not be sensed abnormally with the risk of scalding.

1. Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014 Dec;155(12):2461-2470. doi: 10.1016/j.pain.2014.09.020. Epub 2014 Sep 23. PMID: 25261162.
2. Andersen Hammond E, Pitz M, Steinfeld K, Lambert P, Shay B. An Exploratory Randomized Trial of Physical Therapy for the Treatment of Chemotherapy-Induced Peripheral Neuropathy. Neurorehabilitation and Neural Repair. 2020;34(3):235-246. doi:10.1177/1545968319899918
3. Brayall, Patrick SPT1; Donlon, Erin SPT2; Doyle, Lisa PT, DPT, MS3; Leiby, Renee SPT4; Violette, Katelyn SPT5. Physical Therapy–Based Interventions Improve Balance, Function, Symptoms, and Quality of Life in Patients With Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review. Rehabilitation Oncology 36(3):p 161-166, July 2018. | DOI: 10.1097/01.REO.0000000000000111
4. Niemand EA, Cochrane ME, Eksteen CA. Physiotherapy management of chemotherapy-induced peripheral neuropathy in Pretoria, South Africa. S Afr J Physiother. 2020 Oct 6;76(1):1482. doi: 10.4102/sajp.v76i1.1482. PMID: 33102888; PMCID: PMC7565663
5. Tamburin S, Park SB, Schenone A, Mantovani E, Hamedani M, Alberti P, Yildiz-Kabak V, Kleckner IR, Kolb N, Mazzucchelli M, McNeish BL, Argyriou AA, Cavaletti G, Hoke A; Toxic Neuropathy Consortium. Rehabilitation, exercise, and related non-pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: Systematic review and evidence-based recommendations. Crit Rev Oncol Hematol. 2022 Mar;171:103575. doi: 10.1016/j.critrevonc.2021.103575. Epub 2021 Dec 28. PMID: 34968623; PMCID: PMC10658987
6. Fallon MT, Storey DJ, Krishan A, Weir CJ, Mitchell R, Fleetwood-Walker SM, Scott AC, Colvin LA. Cancer treatment-related neuropathic pain: proof of concept study with menthol--a TRPM8 agonist. Support Care Cancer. 2015 Sep;23(9):2769-77. doi: 10.1007/s00520-015-2642-8. Epub 2015 Feb 15. PMID: 25680765; PMCID: PMC4519585.in Cancer 2015; 23(9): 2769-2777 doi: 10.1007/s00520-015-2642-8
7. Klinkhamer, L, Fallon M. RCT of Menthol in Neuropathic Pain Trial (MINT Trial) to be presented at EAPC, Barcelona 2024.
8. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL; Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013 Apr 3;309(13):1359-67. doi: 10.1001/jama.2013.2813. PMID: 23549581; PMCID: PMC3912515
9. Stringer J, Ryder WD, Mackereth PA, Misra V, Wardley AM. A randomised, pragmatic clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (ACUFOCIN). Eur J Oncol Nurs. 2022 Oct;60:102171. doi: 10.1016/j.ejon.2022.102171. Epub 2022 Jul 11. PMID: 35952460; PMCID: PMC9592667.