by Glare, P., Aubrey, K., Gulati, A. et al.
Excerpt from the article published in Drugs (2022). https://doi.org/10.1007/s40265-022-01675-6
- Chronic pain following cancer treatment is common. It is estimated there are almost 20 million cancer survivors in the USA alone, and some 40% live with chronic pain after completing treatment
- Although many different types of normal tissue may be damaged by cancer treatment, nerve damage is common
- Cancer patients often require initiation of opioid treatment for relief of moderate-severe pain arising during their diagnostic work-up and treatment.
Improvements in screening, diagnosis and treatment of cancer has seen cancer mortality substantially diminish in the past three decades. It is estimated there are almost 20 million cancer survivors in the USA alone, but some 40% live with chronic pain after completing treatment. While a broad definition of survivorship that includes all people living with, through, and beyond a cancer diagnosis—including those with active cancer—is often used, this narrative review primarily focuses on the management of pain in people who are disease-free after completing primary cancer treatment as adults. Chronic pain in this population needs a different approach to that used for people with a limited prognosis. After describing the common chronic pain syndromes caused by cancer treatment, and the pathophysiologic mechanisms involved, the pharmacologic management of entities such as post-surgical pain, chemotherapy-induced neuropathy, aromatase inhibitor musculoskeletal syndrome and checkpoint inhibitor-related pain are described. The challenges associated with opioid prescribing in this population are given special attention. Expert guidelines on pain management in cancer survivors now recommend a combination of pharmacologic and non-pharmacologic modalities, and these are also briefly covered.
Advances in cancer management (earlier detection and better treatment) in the past 30 years have seen cancer change from a terminal illness to a chronic one. In the United States, the National Cancer Institute (NCI) estimates there was a 31% decrease in cancer mortality between 1990 and 2018, with approximately two-thirds people with cancer now living 5 years beyond diagnosis . According to Cancer Research UK, half the people diagnosed with cancer in Britain will live at least 10 years (https://www.cancerresearchuk.org/health-professional/cancer-statistics/survival, accessed 22 November 2021). As a result of the decrease in cancer mortality, the number of cancer survivors has increased, in the case of the United States from approximately 3 million in 1971 to more than 15 million in 2016 . These numbers are predicted to exceed 20 million by 2026 and 26 million by 2040.
Unfortunately, improved cancer survival comes at a cost as patients may experience adverse physical and psychosocial effects from the diagnosis and its treatment. These adverse effects can be severe, debilitating and persistent, sometimes permanent. Pain is one such adverse effect and all modalities of cancer treatment—surgery, chemotherapy, radiation therapy (RT), transplants and immunotherapy—can be painful. Acute pain becomes chronic in approximately 10–20% cases , causing distress and disability that reduces the quality of life long term.
Twenty years ago, when the outlook of a cancer diagnosis was less optimistic, cancer treatment-related pain was classified as a subset of cancer pain and was mainly treated with opioids . Nowadays, the use of opioids in cancer survivors with chronic pain is raising the same concerns as it does in patients with chronic non-malignant pain. This is especially so when the patient has completed definitive treatment for early-stage disease and the prognosis is good . Furthermore, there is increasing recognition that chronic non-malignant pain is a common comorbidity in cancer survivors  and opioids are no longer recommended for this condition . Consequently, the American Society of Clinical Oncology (ASCO) guideline on the management of pain in cancer survivors ranks opioids as third-line treatment .
Numerous reviews of the broad topic of pain in cancer survivors have been published. Some are comprehensive , while others focus on specific issues. Subsequent to the ASCO guideline being published in 2016, there have been a small number of broad reviews of survivor pain treatment [10, 11]. The aim of this narrative review is to provide an update of the etiology and management of chronic pain in cancer survivors, with the emphasis of management being on pharmacological treatments. However, because pharmacological approaches are not effective in all cases, some non-pharmacological approaches are also presented. This review is restricted to pain in survivors of adult cancers; pain in survivors of paediatric cancer has been reviewed recently by others .
Neuropathic Pain After Cancer Treatment
Although many different types of normal tissue may be damaged by cancer treatment, nerve damage is common. It can follow the conventional cancer treatment modalities of surgery, chemotherapy and/or RT.
Persistent Pain Post-cancer Surgery
Chronic pain has been reported after almost all types of surgery, with a higher prevalence (> 20%) reported in sites that are common surgical fields in oncology, such as breast, thorax and spine . While the high prevalence of persistent pain post-cancer surgery is often attributed to iatrogenic nerve injury, there are other contributors including central sensitization and comorbid pre-existing pain in the operated area .
Persistent pain post-breast cancer surgery (PPPBCS, also known as post-mastectomy syndrome) is perhaps the most well documented cancer treatment pain syndrome, with many studies and reviews of the topic being published in the past two decades. PPPBCS has been estimated to affect as many as two women in three, and is moderate to severe in 15–20% of cases 1-year post-surgery . The exact mechanism of PPPBCS is unknown, but is usually attributed to damage of nerves such as in the chest wall or axilla (e.g. intercostobrachial nerve) during surgery. Consequently, it is often reported with typical neuropathic descriptors, such as burning, shooting, as well as mechanical allodynia and deep blunt pain. PPPBCS can begin shortly after surgery but may not come on for several months and can go on for years. In fact, pain is more common after minimally invasive surgery (lumpectomy) than mastectomy. It may be located in the axilla, the shoulder, arm or chest wall. Risk factors include young age, axillary dissection and sectioning of the intercostobrachial nerve. Introduction of sentinel node biopsy has reduced but not eliminated the prevalence of PPPBCS .
Validated prediction models have been developed to screen for patients at high risk of developing PPPBCS. In one model, preoperative pain in the operative area (p < 0.001), high body mass index (p = 0.039), axillary lymph node dissection (p = 0.008) and more severe acute postoperative pain intensity at the seventh postoperative day (p = 0.003) were included in the final prediction model . An online risk calculator has been developed to operationalize the model. Machine learning has also been utilized in predicting PPPBCS, with 21 single or aggregated parameters being identified including demographic features, pain-related variables and psychological characteristics. This method had a cross-validated accuracy of 86% and a negative predictive value of approximately 95% .
Post-thoracotomy pain syndrome (PTPS) occurs with a prevalence ranging from 25 to 57%, although severe in < 10% . Post-thoracotomy pain is predominantly neuropathic in nature, and as with PPPBCS, the etiology is usually attributed to surgical nerve damage, being less common after minimally invasive surgery (e.g. videoscopic-assisted surgery) than open thoracotomy. Unlike PPPBCS, preoperative risk stratification of susceptible individuals for PTPS is not well established . Adjuvant radiation and chemotherapy appear to predispose patients to developing chronic PTPS. Poor postoperative pain management (first 24 hours after surgery) was the sole factor that predicted the development and severity of long-term pain. Psychologic factors are also important, including preoperative anxiety, somatization and pain catastrophizing .
Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Neuropathy is one of the most common complications of chemotherapy. Several classes of chemotherapeutic agents are neurotoxic, including the platinum-based compounds, taxanes, vinca alkaloids, thalidomide derivatives and proteasome inhibitors. Newer classes of chemotherapeutic agents including molecular-targeted agents like ado-trastuzumab emtansine, brentuximab vedotin and the checkpoint inhibitors have also been associated with the development of neuropathic pain . Although these agents are neurotoxic due to various pathological mechanisms (see Sect. 3.1.3), clinically they tend to all present as a symmetrical sensory-predominant peripheral neuropathy that may be associated with significant pain. Some 60% of individuals exposed to neurotoxic chemotherapy agents develop CIPN . In one recent study, the type of chemotherapy (most common after platinum‐based chemotherapy) and number of cycles received was associated with a higher incidence of CIPN . A number of non-chemotherapy-related risk factors have also been identified. Older age, history of pre-existing neuropathy, symptom burden and alcohol intake were independent risk factors on multivariate analysis. Statins and diabetes mellitus were implicated on univariate analysis . Smoking, abnormal creatinine clearance and specific sensory changes during chemotherapy have also been implicated. Although the prevalence of CIPN decreases with time, 30% of patients report it 6 months post-treatment . Those surviving > 5 years often continue to have substantial impairments .
Chronic Pain Post-radiation Therapy
While RT plays an important role in palliation of painful cancer deposits, it may also be the source of treatment-related pain, albeit rarely. Its occurrence is better recognized with improved long-term cancer survival. Onset can be within a few months of the end of RT or up to several years later. Chronic enteritis, cystitis, proctitis, osteoradionecrosis, pelvic fractures and chest wall pain are all described, along with various neuropathic pains (plexopathies, peripheral nerve entrapments and myelopathy) . Risk factors include large overall treatment dose, large dose per RT fraction and combined treatment with surgery or chemotherapy.
Although overall the incidence of post-RT pain is falling, nevertheless, it occurs in 2% of breast cancer survivors and up to 15% of head and neck cancer survivors .
The most widely recognized form of post-RT pain is chronic neuropathic pain after breast cancer treatment . Chronic painful radiation-induced neuropathies usually occur several years after RT and are often progressive and irreversible. Brachial plexopathy is more common after treatment of apical lung cancer (incidence 12% at 3 years)  than breast cancer . Symptoms of post-RT brachial plexopathy begin any time from 6 months to 20 years (median time 1.5 years) after treatment and progressive weakness is common. In the past, pain has been documented as severe enough to need opioids in 50% of cases.
Chronic pain is also described after RT for head and neck cancer , gynaecological cancer  and prostate cancer . Despite advances in RT techniques, patients with head and neck cancer may experience oral complications up to 6 months later, with resulting negative impacts on oral function and quality of life. In a prospective, multi-centre, longitudinal cohort study of 372 patients with head and neck cancer who received high-dose RT with curative intent, mean overall pain score was unchanged from baseline at 6 months in 216 evaluable patients, although it was mild on average (score only 9.2 ± 17.7 on a 0–100 score) . Patients also complained of other persisting symptoms impairing oral health-related quality of life at 6 months including dry mouth, sticky saliva, difficulty swallowing solid foods and dysgeusia. Gynaecological cancer survivors can develop lumbosacral plexopathy after pelvic RT and axial neuropathy of the spinal cord after cervical RT. Women previously treated with pelvic radiation report a higher occurrence of symptoms from the urinary and gastrointestinal tract as well as lymphedema, sexual dysfunction and pelvic pain. In a Scandinavian study that compared women who had been treated for various gynaecological malignancies (> 80% of whom had endometrial or cervical cancer) and were on average 6 years out from completing RT with age-matched controls who had not been treated for cancer, the most prevalent problems were pelvic bone pain (39%), dyspareunia (17%), abdominal pain (12%), dysuria (10%) and genital pain (5%) . While erectile dysfunction is the most well-known side effect of RT for prostate cancer, other changes in sexual function may occur, including orgasm-associated pain (15%) and painful erections (6%) . Penile paraesthesias or cold sensations occurred in 2%. Increasing time since final treatment increased the risk of penile sensory disturbances.
Current Approaches to the Pharmacotherapy of Chronic Pain in Cancer Survivors
Choosing the best pain management strategy for a cancer survivor is complex. It is important to take into consideration the potential impact of pain medications on health, physical and mental states, health behaviours, professional and personal identity, sexuality and financial standing.
Cancer patients often require initiation of opioid treatment for relief of moderate-severe pain arising during their diagnostic work-up and treatment. However, the role of long-term opioid therapy (LTOT) in cancer survivors, especially those who are disease-free after completing definitive treatment, is unclear. According to some, it raises the same concerns as it does in people with chronic non-malignant pain . Chronic opioid use is also associated with chronic constipation, mental clouding, hypogonadism, effects on sexual desire and fertility, sleep disorders, hyperalgesia, and tolerance, misuse and abuse. Chronic use of opioids by long-term survivors may interfere with employment, family dynamics and personal identity. Possible personal implications of chronic opioid use include fear of substance abuse, substance abuse relapse, and the social cost of accepting pain medications during treatment if in a recovery community, especially for survivors who require opioid replacement therapy with buprenorphine or methadone for opioid use disorder (OUD). Key points for using long-term opioid therapy in cancer survivors are summarized in Table 3.
LTOT would not be recommended in cancer survivors who have chronic pain from pre-existing non-malignant comorbidities such as osteoarthritis, spondylosis or migraine because they are considered ineffective for this purpose . Concomitant non-cancer pain is common in cancer survivors  and it can be exacerbated by the deconditioning that follows cancer treatment. These patients need a full diagnostic workup using a biopsychosocial approach and should be treated congruent with the etiology of pain. Opioids would only be recommended in patients with moderate-severe pain that has not responded to maximum tolerated doses of non-opioid therapies [90, 91].
A recent review of persistent opioid use in cancer survivors has found a relationship between LTOT and various clinical factors including cancer type, socioeconomic factors and comorbidities [92, 93]. A national survey in the US found that 5% of opioid prescriptions were for cancer survivors . They were more likely to receive opioids than patients without a cancer history, but they did not have an increased incidence of opioid misuse, which was uncommon, occurring in only 3–4% of both groups. Risk factors for misuse by cancer survivors included younger age (aged 18–34 years vs ≥ 65 years) (OR 7.06; 95% CI 3.03–16.41; p < 0.001), alcohol use disorder (OR 3.22; 95% CI 1.45–7.14; p = 0.005) and non-opioid drug use disorder (OR 14.76; 95% CI 7.40–29.44; p < 0.001) . It is somewhat controversial whether opioid misuse in chronic pain patients, including cancer survivors, is the same entity as OUD in people who use opioids for non-medical purposes. An alternative term, complex persistent opioid dependence (CPOD), is preferred by some to describe this diagnostic entity, which is hard to diagnose by the DSM-V criteria for OUD . CPOD has the same underlying mechanism and responds to the same treatment, with opioid replacement therapy . When opioid misuse does occur in a cancer survivor, it can present a very challenging management problem .
Overdose is the most feared consequence of opioid use. It has been increasing not only in the general population but also among cancer patients . Furthermore, co-involvement of alcohol and/or benzodiazepines in these deaths is common and increasing, reaching 14.7% for alcohol and 21.0% for benzodiazepines in one recent study . Reducing the concomitant use of these agents provides a potential target for policy and practice efforts to reduce opioid-related harms.
Opioid diversion (defined as unlawful channelling of opioids from the patient for whom they were prescribed to others) is also a risk with long-term opioid use, even in cancer survivors. Unused prescription opioids are the primary source of misuse among family members, as well as the community at large . Among family members with OUD, 70% began taking opioids prescribed to a relative and only 30% obtained their drugs of addiction from other sources . However, prescribers do need to take ownership of opioid diversion: the study also showed that for those at the highest risk of overdose—people who use prescription opioids nonmedically 200 or more days a year—the most common way they get opioids is through their own prescriptions (27% of the time), as often as they get the drugs from friends or family for free (26%) or buy them from friends (23%).
Given all these problems, the decision to continue or restart opioids after completing cancer treatment should not be made lightly. When opioids are necessary, the lowest effective dose should be prescribed and as the painful condition resolves, opioids should be tapered down or discontinued in a safe manner.
Reducing or Discontinuing Opioids
In cancer survivors who have been taking opioids for years, tapering may need to be done over a prolonged period—weeks to months or longer. If withdrawal symptoms prevent further dose decrease, the taper should be temporarily halted and resumed when the withdrawal symptoms decrease, and with close monitoring. Observational data suggests that serious harms such as opioid overdose and suicidal ideation can occur following opioid dose reduction or discontinuation, but the incidence of these harms at the population level is unknown . Referral to an addiction specialist, primary care provider or clinic who can prescribe opioid replacement therapy may be helpful for long-term management of OUD or CPOD in a cancer survivor, and new approaches to the transitioning of treatment are being developed .
Monitoring of Long-Term Opioid Therapy
Realistic goals, agreement about safe usage, storage and disposal and frequent reassessment are paramount if opioid therapy is considered for a cancer survivor. Realistic goals include functional pain management outcomes and creation of a strategy to avoid/ minimize the risks related to opioids. Treatment needs to be re-evaluated if treatment goals or safety goals are not met.
- Establish and document desirable functional outcomes.
- Re-evaluate the effectiveness and necessity of opioids on a regular basis.
- If the expected outcome is not achieved, other treatment alternatives should be considered. If opioids are no longer appropriate, recommend gradual tapering of opioids to help avoid symptoms of withdrawal.
- Consider establishing pain treatment agreements.
- Adjuvant medications and non-pharmacological interventions should be considered.
- Use a multimodality approach to pain management if warranted, and if those resources are available. Consider referral to a specialist in interventional pain, physical medicine and rehabilitation, or other appropriate consultants.
- It is important to be aware that pain experience in a cancer survivor can be influenced by both medical and psychosocial events during and after cancer treatment. Psychological support of the survivor with chronic pain is necessary, and referral to psychosocial services should be considered.
Overcoming Barriers to Long-Term Opioid Therapy When It is Clinically Appropriate
Cancer patients are generally excluded from various guidelines suggesting limiting chronic opioid prescribing (https://www.cdc.gov/drugoverdose/pdf/prescribing/Guidelines_Factsheet-a.pdf (last accessed May 22, 2021). In the US, however, 92% of US oncology practices are concerned that restrictions on opioid prescribing to non-cancer pain patients will result in undertreating cancer pain (American Society of Clinical Oncology. 2017 Oncology Practice Census ). About 40% of the oncology practices in the US report new barriers to patients receiving opioids in the pharmacy . If chronic opioids are indicated, the prescriber should provide administrative support to the cancer survivor to ensure appropriate access to opioids.
While new formulations of old drugs have been approved, very few truly novel analgesics have been approved by the US Food and Drug Administration or other regulatory agencies in recent decades. The opioid epidemic is leading to renewed interest in finding new targets . Novel opioids, α-adrenergic agonists and oxytocin have been identified as potential candidates, along with target toxins and gene-based approaches such as protein synthesis blockade and transfection [144, 145]. With regard to cancer treatment-related pain specifically, novel agents are being evaluated for CIPN. MR309, an oral sigma 1 antagonist (sigma-1 is a mitochondrial endoplasmic reticulum receptor), has been shown to reduce chemotherapy-induced mitochondrial structural changes and pain behaviours in lab animals . A randomized phase II clinical trial of MR309 was shown to improve short-term outcomes (decreased cold hypersensitivity) in patients receiving oxaliplatin-based chemotherapy, reducing treatment dropouts and allowed a higher cumulative dose of oxaliplatin to be given . However, its effect on chronic pain outcomes is unknown.
Millions of people are living with chronic pain after completing cancer treatment and the number continues to grow as improvements in cancer treatment continue to be developed. While opioids are the mainstay of pain due to cancer, their use is problematic in disease-free cancer survivors who have been treated with curative intent and have a normal prognosis. If these people have chronic pain, other treatment options should be tried first. …