Moderate-quality evidence suggests that almost half of all women undergoing breast cancer surgery develop persistent post-surgical pain, and about one in four develop moderate-to-severe persistent post-surgical pain; the higher prevalence is associated with axillary lymph node dissection¹.

Key points from evidence: Persistent post breast cancer surgery pain (PPSP) is common. In the latest systematic review and meta-analysis, the authors found that almost half of all women undergoing breast cancer surgery develop persistent pain, and about one in four develop moderate-to-severe pain. The prevalence of PPSP after breast cancer surgery is 46% when considering any location, any severity, and when captured directly from patients; the prevalence of patient reported pain at any location reduces to 27% when restricted to moderate or greater severity. Higher prevalence of persistent pain is associated with axillary lymph node dissection (ALND), likely because of sacrifice of the intercostal brachial nerve. Both prevalence and severity of persistent pain seem to remain stable for over 2 years of available follow up data, suggesting that once PPSP develops, it may be unlikely to improve. It is associated with:

• reduced quality of life
• increased risk of unemployment
• greater healthcare costs

It is clear there is a significant subgroup effect for patient-reported vs clinician-assessed pain; this indicates that clinical assessment – as opposed to patient reported outcomes – may systematically under-estimate pain prevalence.

Evidence demonstrates that PPSP after breast cancer surgery is a major clinical problem.  Preliminary evidence suggests that education, exercise therapy, psychological or behavioural interventions, and paravertebral blocks in addition to general anaesthesia or ketamine infusion perioperatively may reduce the rate of persistent pain after breast cancer surgery; however, this research is ongoing.²

There are several types/combinations of post breast surgery pain and all more common with severing of intercostal brachial nerve (otherwise, the type of surgery seems less important):

1. Post mastectomy pain
2. Pain related to breast conserving surgery
3. Axillary pain
4. Lymphoedema exacerbating surgical pain
5. Tethering of scar due to a combination of factors

In addition to axillary dissection, other potential risk factors are:

1. Radiotherapy and neurotoxic chemotherapy
2. Mood impacting factors such as altered body image.

(Important to note that nerve pain/neuropathic pain anywhere in the body is associated with recruitment of the mood pathway in the brain which will both lower mood and increase pain pathway activity.)

Patients will describe post-surgical pain as usually constant with exacerbations on light touch and/or movement, with pins and needles, shooting pain, burning and other unpleasant sensations in an area which may or may not be numb. Wearing a bra can exacerbate the pain. Physical contact with a partner is usually severely limited or impossible.

Mapping out of the area affected is useful, especially as an initial response to medical management is demonstrated by a shrinkage of the painful area. Examination using a cotton wool ball will often show acute sensitivity to light touch and touching with an alcohol swab will sometimes demonstrate an exaggerated cool response. Areas of numbness can vary and may be painful.

Medical alongside appropriate cognitive management are the cornerstones unless there is a specific, obvious, and reversible surgical cause of pain. Rationale for management approaches below:

Medical management includes gabapentin or pregabalin; tricylclic antidepressants (TCAs) ^†amitriptyline or ^†imipramine, ^†venlafaxine or duloxetine, ^†capsaicin, and Cognitive Behavioural Therapy (CBT). Peripheral nerve injury during surgery can lead to cortical changes in the brain, known as central sensitisation, involved in persistent post-surgical neuropathic pain. Gabapentin, amitriptyline, and venlafaxine were found to offer pain relief for breast cancer patients with chronic pain, by targeting centralized pain pathways. Gabapentin inhibits neuropathic pain through enhancement of GABA activity and decreasing excitable synaptic transmission targets. Key mechanisms of TCAs and SSNRIs (venlafaxine) in neuropathic pain inhibition are:

• Reuptake inhibition of noradrenaline
• Noradrenaline inhibition of neuropathic pain via α2-adrenergic receptors in the dorsal horn of the spinal cord
• Altering noradrenaline levels in the brainstem

Topical treatments studied are menthol and capsaicin creams. Capsaicin’s mechanism of action is reported to be through the attenuation of cutaneous hypersensitivity through a process described as “defunctionalisation.” Menthol works by blocking TRPM8 receptors which increase in peripheral nerve pain. Adverse side effects from capsaicin, such as new burning sensations is commonly reported, which may explain its apparent lack of popularity. Menthol is usually very well tolerated but rarely patients experience excessive coolness.

Behavioural cognitive therapy is theorized to target centralized pain centres. The mechanism of cortical neuromodulation through mindfulness-based therapies has been well studied. Leading explanations for its effect are through reducing expectations of pain and attenuating psychological and neural processes. It is important that we can explain the physical pathways which can be changed in the brain by cognitive/neuromodulatory approaches to result in reduced pain.

Paravertebral blockade and neurolysis are non-surgical methods to address peripheral nerve pain include blockade or neurolysis of C7–T4 stellate ganglions, or pulsed radiofrequency (PRF) of T2–T3 dorsal root ganglia. Thoracic paravertebral blocks achieve immediate but short-term pain relief (<1 month). PRF with steroid injection has an initial slower modulation, due to thermal damage altering synaptic transmission. Blocks may be useful in cases where immediate pain relief is needed, whereas PRF may offer less profound, but longer-term relief. Neither is shown to be curative.

Painful Neuroma peripheral nerve injury can lead to aberrant growth and painful neuroma formation. Nerves at elevated risk of traction and/or laceration injury at the time of mastectomy are the intercostal brachial cutaneous nerve (ICBN), long thoracic, thoracodorsal, lateral branches of the intercostals, lateral, and medial pectoral nerves. The results from reviews indicate that the surgical technique of neuroma excision and implantation can provide long-term relief from chronic neuropathic pain, however a clear diagnosis and appropriate skill are required.

Scar Management (fat transfer, laser, lymphatic surgery) abnormal scarring, such as scar contracture and subcutaneous fibrous adhesions, are recognised as adverse outcomes and may be treated. This phenomenon can be exacerbated by axillary node dissection and adjuvant radiation. Not only does contracture lead to stiffness and decreased mobility, it may compress local peripheral nerves. The promising results from Level I/II fat grafting studies support its use for neuropathic pain relief in breast cancer patients at high risk for scar contracture. However, it remains uncertain if the mechanism of pain relief from fat grafting is scar release which increases suppleness of tissue and decompresses peripheral nerves, and/or stem cell modification. The successful pain relief outcomes from one laser study can be regarded similarly to the results from fat grafting. Treating the skin with a non-ablative laser may release scar contractures through stimulation of the local inflammatory response which increases blood flow, vascular permeability and cell metabolism. Laser therapy may also directly affect local peripheral nerves through a laser induced neural block that causes change in nociception.

While post mastectomy pain syndrome (PMPS) is widely regarded to be a neuropathic disorder, it has been suggested that the musculoskeletal system and myofascial pain may contribute to chronic post-operative pain syndromes.

Muscle fibrosis and increased motor nerve excitability, secondary to inflammation, can create myofascial trigger points (TrPs). Active TrPs have been found in multiple muscles in patients with PMPS, but not in healthy controls.

Physiotherapy programs utilising strengthening exercises and massage are effective for improving shoulder pain by reducing presence of TrPs. The results of reviews support the role of physiotherapy in treating PMPS patients experiencing neck and shoulder/axillary pain and highlight the benefits of water exercises that allow patients to perform exercises they would be unable to perform on land.

Involvement of the neuromuscular junction in chronic myofascial pain is also the basis of studies testing the clinical benefit of botulinum toxin on persistent post-mastectomy pain. There have not been positive studies so far.³

Managing concomitant problems and attenuating impact of radiotherapy is important:

• Management of CIPN is important as CIPN will exacerbate all other pains.
• Low dose oral steroids can be considered during adjuvant breast radiotherapy to reduce peripheral neuro-inflammation which will exacerbate PPSP.

1. Simple analgesia such as paracetamol can be tried and short courses of non-steroidal anti-inflammatory drugs, if no contraindications, can be considered. However, opioids are generally best avoided in this situation.
2. Consider proactive minimisation of impact of breast radiotherapy on breast surgery pain by the use of a short course of steroids if no contraindication. Dexamethasone 2 mg orally per day during radiotherapy may be sufficient.
3. Manage all concomitant problems simultaneously such as lymphoedema techniques, CIPN and any other pain.
4. Trial of ^†lidocaine 5% patches initially to be used for 12 hours out of every 24 hours (if a good response and pain recurs during the 12 hours off and no skin irritation the patches can be used for 24 hours). These work through blocking the sodium channel important in neuropathic pain and not by a local anaesthetic effect. Maximum of 3 patches can be used at one time.
5. Trial of menthol 5% in aqueous cream applied to the painful areas as well as the lower cervical/upper thoracic spine, if it can be reached, twice daily.^3,4
6. Trial of a TENS machine, but not recommended if sensitivity to light touch. However, if massage of the area helps the pain, this can be a good indicator of potential success of use of a TENS machine.  TENS machines may be available through your local pain team, palliative care or supportive care service.
7. Neuropathic agents. There is no evidence for the superiority of a particular neuropathic agent and choice based on any comorbidities:
   1. For a patient with breast pain and CIPN, duloxetine would be the neuropathic agent of choice.
   2. As an antidepressant duloxetine would also be indicated for patients with an associated mood disturbance. 
   3. ^†Venlafaxine may also be helpful with hot flushes.
   4. Pregabalin is licensed for general anxiety disorder, so can be considered in the very anxious patient who has difficulty sleeping. Pregabalin or gabapentin could be tried in patients where there is a contraindication to duloxetine.
8. Trial of a high dose topical ^†capsaicin 8% patch to the painful area can be considered in those patients not responding to the above, or who wish to avoid oral medication. This is a one-off treatment which, if effective, lasts for 3 months; if repeat treatment is required, the area requiring treatment has often shrunk. The treatment itself takes an hour and can be carried out by appropriately experienced palliative care clinician (doctor of nurse) or chronic pain team clinician. (A trial of capsaicin cream can precede the patch but is not predictive of effect of patch).
9. There is some evidence for acupuncture for scar pain and if locally available this would usually be at one treatment per week for 6 weeks.⁵

Patients can be told that with appropriate treatment and control or significant attenuation of the pain for a period of at least 3 months can be followed by a trial of stopping treatment.  Effective early control usually means that ongoing chronic pain can be avoided.

1. Wang L, Cohen JC, Devasenapathy N, Hong BY, Kheyson S, Lu D, Oparin Y, Kennedy SA, Romerosa B, Arora N, Kwon HY, Jackson K, Prasad M, Jayasekera D, Li A, Guarna G, Natalwalla S, Couban RJ, Reid S, Khan JS, McGillion M, Busse JW. Prevalence and intensity of persistent post-surgical pain following breast cancer surgery: a systematic review and meta-analysis of observational studies. Br J Anaesth. 2020 Sep;125(3):346-357. doi: 10.1016/j.bja.2020.04.088. Epub 2020 Jun 28. PMID: 32611524.
2. Chappell AG, Yuksel S, Sasson DC, Wescott AB, Connor LM, Ellis MF. Post-Mastectomy Pain Syndrome: An Up-to-Date Review of Treatment Outcomes. JPRAS Open. 2021 Aug 11;30:97-109. doi: 10.1016/j.jpra.2021.07.006. PMID: 34522756; PMCID: PMC8426165.
3. 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
4. Klinkhamer, L, Fallon M. RCT of Menthol in Neuropathic Pain Trial (MINT Trial) to be presented at EAPC, Barcelona 2024.
5. 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.