13.5 Management issues in chronic pain following cancer therapy

The extended phase of cancer survivorship commences after completion of initial anti-cancer treatment and includes regular follow-up examinations with or without maintenance or intermittent anticancer therapy. The permanent survival phase follows the extended phase and continues until death (Levy et al., 2008).

The American Cancer Society have stated that their goal is to make cancer into a chronic disease state in which long-term control is possible, even in the absence of a conventional cure (Burton et al., 2007). At a global level, the incidence of 26 cancers in 2008 was estimated at 12.7 million new cancers by GLOBOCAN series of the International Agency for Research on Cancer (World Health Organization (WHO), 2008). Survival at 5 years after diagnosis is the widely used benchmark for prevalence. Accordingly, there were an estimated 24.6 million people worldwide living with cancer in 2002 (Parkin et al., 2005; WHO, 2005). As of January 2008, it is estimated that there are 11.9 million cancer survivors in the United States. This represents approximately 4% of the population, with approximately 15% of these cancer survivors being diagnosed 20 or more years earlier (Howlader and Noone, 2009).

Improved cancer surveillance, more accurate diagnoses, more efficacious treatment, as well as longer follow-up, have led to an increased life expectancy for patients and increased number of ‘cancer cured’ people. It is predicted that this number of cancer survivors will increase in the future. A public health effort to address cancer survivorship supports the Healthy People 2010 goal to increase the proportion of cancer survivors who are living 5 years or longer after diagnosis to 70% (US Department of Health and Human Services, 2010).

The report from the Institute of Medicine ‘From Cancer Patient to Cancer Survivor: Lost in Transition’ mentions that although the number of patients surviving cancer is increasing, it is unknown what this will mean to the health and well-being of these people (National Research Council, 2005).

Survivors face numerous physical, psychological, social, spiritual, and financial issues following their diagnosis and treatment and for the remaining years of their lives. The health-care challenges of survivors are being now recognized as unique. In addition to the acute effects of the surgical, radiation, and chemotherapy treatments, many permanent phase survivors are at risk for developing late or long-term side effects from their primary treatments. These long-term effects have a bearing on obtaining optimal physical, psychological, and cognitive functioning for survivors—which is the goal of rehabilitation for patients with cancer (Chasen and Dippenaar, 2008). Survivors of cancer have significantly poorer health outcomes across many burden of illness outcomes for many years after the diagnosis of cancer (Miaskowski and Dibble, 1995; Siddall and Cousins, 2004). More than 6 million survivors are older than 65 years, thus translating into a growing elderly patient population of cancer survivors who suffer from co-morbidities that affect their general well-being (Deimling et al., 2007). For many survivors, a high prevalence of physical symptoms, in addition to symptoms in other life domains will diminish their quality of life (Alfano and Rowland, 2006).

Pain is recognized as impacting on all dimensions of quality of life (Cleeland, 1984; Miaskowski and Dibble, 1995; Siddall and Cousins, 2004; Burton et al., 2007) and is one of the most distressing symptoms for patients with cancer (Patrick et al., 2003; Sun et al., 2008). Pain, may, in some cases of head and neck cancer patients predict for survival (Funk et al., 2012). Up to 40% of 5-year cancer survivors report pain (Nelson et al., 2001; Anderson et al., 2002). Experiencing pain was related to poorer general health (p = 0.001) and physical (p < 0.001), role (p < 0.01), and social (p < 0.001) functioning in a group of patients who had survived cancer (Green et al., 2011).

Patients under-recognize pain and are often unsure if optimum pain control is achievable Green et al., (2002, 2003). They are concerned about distracting attention away from treatment and believe that pain is indicative of progressive disease (Turk, 2002; Green et al., 2003, 2009; Greenberg et al., 2003; Stewart et al., 2003; Howlader and Noone, 2009). In addition, members of the interdisciplinary team often fail to assess the patient’s pain adequately or to recognize under reporting (Anderson et al., 2000; Nelson et al., 2001). Many professionals lack knowledge of the principles of pain relief, side effect management, or understanding of key concepts like addiction, tolerance, dosing, and communication (Green et al., 2009). Epidemiological data including incidence and prevalence of chronic pain in the different cancer types have not been reported consistently and pain treatment strategies such as the WHO pain ladder has not been validated for patients with cancer who have chronic pain (Burton et al., 2007).

Chronic pain in cancer survivors can arise because of damage to tissue caused by the cancer and/or the cancer therapy: surgery, chemotherapy, steroids, hormones, and radiation (Table 13.5.1). In addition, survivors may have pain from chronic conditions such as post-herpetic neuralgia, rheumatic diseases and diabetic neuropathy. At one centre, up to 40% of visits to a Cancer Survivors Pain and Palliative Care Program were due to chronic pain.

Chronic pain in cancer survivors can be divided into three pathophysiologic categories: somatic, visceral, and neuropathic (Levy et al., 2008):

CIPN affects up to 96% of patients who receive potentially neurotoxic chemotherapy (e.g. platinums, taxanes, vinca-alkaloids, and bortezomib), resulting in dose-reduction or early cessation of potentially life-prolonging treatment for up to 50% (Vasey et al., 2004; Richardson et al., 2006; Argyriou et al., 2008; Storey et al., 2010). Symptoms are commonly in a glove and stocking distribution and include spontaneous pain, paraesthesia, allodynia (non-painful stimuli causing pain), hyperalgesia (increased sensitivity to painful stimuli), hypoaesthesia (numbness), and impaired proprioception, causing difficulty with day-to-day functioning such as fastening buttons, handling coins, walking and driving. One year following cessation of treatment approximately 50% of patients still have symptoms which both limits future treatment options for patients with relapsed/metastatic disease and leaves many with long-term pain or disability despite being cured of cancer. In our centre 57% of colorectal cancer patients still had symptoms of neuropathy 6 months after completing treatment with curative intent (WHO, 2005).

Estimates for persistent neuropathic pain after cancer surgery vary, with post-mastectomy and post-thoracotomy pain occurring in 30–60% of patients (Kehlet et al., 2006). One large study after breast cancer surgery found almost half of patients had persistent pain 2–3 years later, with this being moderate to severe in nearly a quarter of (Gartner et al., 2009). In our own centre approximately 30% of patients had persistent post-mastectomy pain, with a threefold increase in risk conferred by adjuvant chemotherapy (Sheridan et al., 2012). Recent guidelines suggest the use of objective quantifiable tests such as Quantitative Sensory Testing as clinical biomarkers to strengthen the diagnosis of neuropathic pain, which is made on history and examination (Smith et al., 2007; Cruccu et al., 2010; Haanpaa et al., 2011).

Treatment of neuropathic pain relies on early identification, understanding of the initiating and sustaining pathophysiological mechanisms and use of a range of therapeutic approaches (Attal et al., 2011). Evidence is accumulating which suggests the neurosensory characteristics of the pain may be the most important factor in predicting a treatment response, rather than the underlying aetiology (Dworkin et al., 2011; Selph et al., 2011). Current systemic therapy is mainly oral antidepressants or anticonvulsants; however, treatment often requires titration over months and is limited by variable efficacy and unacceptable side effects (Liu and Qin, 2011).

Cervical lymph node metastases in this setting have been treated commonly with radical neck dissection, which involves the removal of the ipsilateral spinal accessory nerve (cranial nerve CN) XI), internal jugular vein, and sternocleidomastoid muscle, in addition to ipsilateral cervical lymph node groups. Though performed commonly, this procedure carries with it significant morbidity.

The ‘shoulder syndrome’ manifests as continuous pain, shoulder tilt and drop, limitations in shoulder retraction, anterior flexion movements and active shoulder abduction, winged scapula and abnormal electromyographic findings (Ewing and Martin, 1952). Compromise or injury to the spinal accessory nerve (CN XI) can result in sensory paraesthesias and numbness. It has been observed that patients who have undergone neck dissections sparing the spinal accessory nerve, report less shoulder and neck pain than those in whom it was sacrificed. Spinal accessory nerve preservation has also been correlated with lower consumption of analgesics (Terrell et al., 2000).

Nonetheless, chronic pain has been demonstrated even with sparing of the spinal accessory nerve, as evidenced by electromyographic studies. This is most commonly secondary to expansive dissection, vigorous traction, intraoperative trauma, and ischaemia (Sakorafas et al., 2010). Morbidity is compounded if there is a delay in the diagnosis post surgery.

Osteonecrosis of the jaw is a known potential adverse effect of head and neck irradiation. It can be exacerbated by the use of steroids and chemotherapeutic agents, infection, periodontal disease, and poor dental hygiene. It has been associated more recently with the use of high doses of intravenous bisphosphonates in several studies, with the mandible being the most commonly affected site.

Patients who have had radiation to the pelvis for rectal cancer can be at risk of the development of ‘pelvic pain syndrome’. Aetiologies for this syndrome may include chronic radiation enteritis or proctitis, chronic cystitis, pelvic insufficiency fractures, and neuropathies which may manifest as burning perineum syndrome (Levy et al., 2008).

Chronic radiation enteritis can happen in up to 15% of patients receiving abdominal or pelvic irradiation. The onset of symptoms may occur up to 18 months post radiation treatment, and commonly include crampy, colicky abdominal pain accompanied by tenesmus, bloody diarrhoea, emesis, and anorexia or weight loss.

Cystitis, the product of chronic effects of bladder irradiation, results from endothelial ischaemic damage and interstitial fibrosis, and may lead to a diminution in bladder capacity. Clinically, urgency and dysuria may be observed.

Pelvic insufficiency fractures are an uncommon side effect of chemotherapy and radiation treatment for rectal cancer, however they can lead to significant morbidity. Pain is usually intense and of acute onset, most commonly affecting the abdomen, low back, pelvis, hip, buttock or thigh. Studies indicate a 3-year average of 3.1%, and females and Caucasians appear to be at higher risk (Herman et al., 2009). Burning perineum syndrome refers to pain that has developed in the perianal region as a result of radiation that may expand to encompass the scrotum or vagina. It is a rare complication, and onset is usually 6 to 18 months following radiation (Minsky and Cohen, 1988).

Depending on the disease presentation, limb-sparing surgery may be an option for soft tissue sarcomas occurring in an extremity, and thus amputation may not be necessary. Certain situations will, however, dictate limb amputation.

One of the more frequent complications post amputation is phantom limb pain (PLP), the perception of painful sensations in an amputated extremity. Though the exact mechanism is unknown, it is believed to be secondary to spinal plasticity and cerebral reorganization following an insult. Onset is typically within days to weeks of amputation, but can be delayed for months or years. It has been shown to occur acutely in over half of amputees, with higher levels of extremity amputation increasing the risk of greater pain intensity. Incidence is higher following traumatic amputation as opposed to surgical amputation (Ramachandran and Hirstein, 1998). Other risk factors include the presence of pre-amputation pain, persistent stump pain, noxious intraoperative stimuli and acute postoperative pain (Ramachandran and Hirstein, 1997). PLP is less common in children and congenital amputees. Phantom limb pain can be varied in presentation, but may be shooting, stabbing, cramping, burning, or itchy in nature. Pain is often localized to the distal portion of the amputated extremity, and many patients report that the affected limb is in a contorted or awkward position. Some patients have also reported exacerbations with cold temperature, stress, fatigue, urination, and defecation. Psychological factors are not correlated with its occurrence, but may be exacerbating rather than causative in nature.

The treatment modalities available for prostate cancer have expanded within the last several years. Standard treatment is androgen deprivation therapy, either surgical (orchidectomy) or medical (gonadotropin-releasing hormone (GnRH) agonist treatment). The intended outcome of GnRH agonist treatment is hypogonadism, which is a significant cause of acquired osteoporosis in males. GnRH agonists have been shown to decrease bone mineral density of the hip and spine by approximately 2–3% per year during initial treatment. Similarly, surgical orchidectomy for prostate cancer is often followed by severe osteoporosis and increased risk of hip fracture and vertebral fracture. Risk factors include Caucasian race, low bone mineral density, and treatment duration of at least 1 year with GnRH agonists (Smith et al., 2005; Saylor et al., 2011). This increased risk starts almost immediately and can persist for several years (Daniell, 1997).

Chronic testicular pain is a well-known potential complication of treatment for testicular cancer. This includes chronic pelvic pain syndrome (pelvic pain either continuous or recurrent for at least 6 months) and phantom testes syndrome (pain in the removed testis), with the presence of preoperative pain in the removed testes as a positive risk factor (Puhse et al., 2010). A higher incidence of genital pain during and after intercourse has also been recorded (Puhse et al., 2008).

Treatments for breast cancer now commonly include surgery for axillary node dissection and primary tumour staging, radiation, hormonal (anti-oestrogen) therapy, and/or chemotherapy. Up to half of patients post mastectomy experience chronic pain, which can lead to significant encroachments on a patient’s quality of life due to physical and emotional distress. Chronic neuropathic pain following mastectomy has been well documented and can be characterized by four different types of pain syndrome:

Chronic post-thoracotomy pain syndrome (PTPS) is a persistent or recurrent pain in the area of a thoracotomy incision for at least 2 months following surgery (International Association for the Study of Pain, Subcommittee on Taxonomy, 1986). It is believed to be secondary to intercostal nerve damage as well as suboptimal control of acute pain in the immediate postoperative period. Aggressive rib retraction may also contribute by leading to costovertebral and costochondral dislocation. Neuroma formation and tumour recurrence have also been cited. The syndrome is characterized by significant burning pain with other associated neuropathic features postoperatively with a very slow resolution in the following months and years. Unfortunately, it does not appear to decrease appreciably with time. There is a relatively high incidence of ipsilateral arm and shoulder dysfunction. The incidence of PTPS is reported at approximately 80% at 3 months, 75% at 6 months, and 61% 1 year after surgery (Perttunen et al., 1999). One study found that approximately 30% of patients continued to report pain at 5 years post thoracotomy with no significant decrease in pain intensity (Dajczman et al., 1991). Preoperative epidural analgesia has been shown to be more effective at reducing the incidence and intensity of the resultant chronic pain than postoperative epidural analgesia (Obata et al., 1999).

Haematological malignancy survivors are at an increased risk of developing chronic pain syndromes due to several potential treatment related complications. These pain syndromes are of particular concern in the setting of stem cell transplantation, given the treatment intensity. Patients may experience significant bone pain as a result of prolonged steroid therapy as treatment for graft-versus-host disease. This may lead to an increased incidence of osteonecrosis and osteoporosis. Haemorrhagic cystitis is another painful condition, which can result from certain conditioning regimens, especially those containing cyclophosphamide and total body irradiation. The immune-suppressing calcineurin inhibitors used prophylactically post stem cell transplant to prevent graft rejection (i.e. cyclosporine, tacrolimus) can have neurotoxic side effects with an incidence between 5% and 30%. Profound immune suppression post transplant leaves patients susceptible to a number of opportunistic infections, such as herpes zoster, with the potential subsequent development of post herpetic neuralgia (Niscola et al., 2008).

Despite numerous advances in the course of the last several years, the management of chronic pain in cancer survivors is often suboptimal, secondary to the complex neurophysiology of many chronic pain syndromes and a relative paucity of education and resources within many oncological settings. It requires an interprofessional approach that details a comprehensive assessment with ongoing reassessment to guide the implementation and integration of pharmacological and non-pharmacological measures. This facilitates the elucidation and revision of the pain source, alteration of the perception of pain, and inhibition of pain transmission to the central nervous system (Ferrer-Brechner et al., 1985), thereby helping to optimize patient quality of life.

Opioid therapy is one of the foundations of cancer pain treatment. Its role in the management of neuropathic as well as nociceptive pain has been confirmed in several clinical trials (Eisenberg et al., 2005). Though morphine remains the most widely used opioid, there is presently no evidence to suggest that one opioid is better than another as a first-line agent. Opioid therapy can be administered through several routes, including oral, transdermal and, most commonly, parenteral. Opioids can also be delivered via the buccal, submucosal, and intranasal routes (rapid onset opioids), and rectally for the control of episodes of breakthrough pain, in addition to regularly scheduled or long-acting preparations. Methadone may have a distinctive role in the management of chronic pain in cancer survivors due to its action as an opioid agonist and N-methyl-D-aspartase (NMDA) receptor antagonist, which can inhibit central sensitization and may moderate allodynia and hyperalgesia in certain neuropathic pain syndromes. In occasional situations, neuraxial (epidural or intrathecal) delivery of opioids may be appropriate for some particularly challenging pain syndromes when resources permit.

When opioids are used as a singular treatment, higher doses may be required. This may lead to adverse effects such as constipation and sedation, as well as long-term complications, which can include tolerance, opioid-induced neurotoxicity, physical dependency, and pituitary axis suppression. Clearly in susceptible individuals, psychological dependence may become an issue. Optimal management of neuropathic pain usually involves the administration of a neuropathic analgesic medication, used either alone or in combination with opioids for synergistic effect, which may reduce the risk of opioid-induced neurotoxicity. Those used most commonly in this setting include antidepressants, anticonvulsants, and non-steroidal anti-inflammatory drugs (NSAIDs).

Tricyclic antidepressants (TCAs) such as nortriptyline and desipramine are used most commonly in the setting of neuropathic pain, as they have a lower incidence of anticholinergic and cardiac side effects (QT prolongation) as compared to amitriptyline. Usually days to weeks of treatment are required before a measurable degree of analgesia is achieved. Newer classes of antidepressants including serotonin and norepinephrine (noradrenaline) reuptake inhibitors (i.e. duloxetine and venlafaxine) can also have a role in the modulation of neuropathic pain, however selective serotonin reuptake inhibitors (SSRIs) have not been proven to be as effective (Sindrup et al., 2005). (See Chapter 13.3.)

Anticonvulsant medications commonly used in the management of neuropathic pain include gabapentin, carbamazepine, and pregabalin. Carbamazepine is thought to exert its analgesic effect through the reduction of conductance in sodium channels and may have a particular role in the management of trigeminal neuralgia. Gabapentin and pregabalin are similar in their mechanism of action, which appears to be delivered via interaction with the α2-δ protein subunit of voltage-gated calcium channels. Pregabalin displays linear absorption as opposed to gabapentin, giving it a more predictable dose response range and a generally faster time to therapeutic titration. The efficacy of other anticonvulsants for neuropathic pain has not been reliably established in clinical trials.

Anti-inflammatory agents (NSAIDs, steroids) have been employed in several chronic pain syndromes in cancer survivors. They are mostly used in association with opioids for musculoskeletal pain; however they are not viable options for long-term treatment due to side effects. Other potential treatments being explored include topical analgesics such as lidocaine and the NMDA receptor antagonists such as ketamine. These treatments require further research.

Non-pharmacological treatment options should be used in combination with medications where appropriate, with a view to minimizing medication side effects and optimizing function and quality of life.

The basic concept of a true multidisciplinary, interdisciplinary treatment team to manage and address the challenges and the various needs of cancer survivors, including pain, is a natural progression based on the cancer rehabilitation philosophy. The latter’s objective being, through an interdisciplinary approach, to empower individuals who are experiencing loss of function, fatigue, pain, malnutrition, psychological distress, and other symptoms, as a result of cancer or its treatment to improve their own quality of life (Chasen and Dippenaar, 2008). Such teams have shown efficacy in treating chronic pain in the general population (Shealy, 2013). The results have been profound with at least one-third returning to work, their average pain intensity decreasing an average of 70% and their mood improving in 90% of patients. This same interdisciplinary treatment prototype also can be applied to cancer survivors (Robbins et al., 2003). Team members should include physicians, nurses, physical, occupational, and vocational therapists in addition to dietitians, social workers, and psychologists. The different disciplines involved in the care of these patients constitute the team. It is vital that communication within the team is open, direct, and supportive. Herein lies the strength of collaboration between team members. They will learn of the different assessment approaches, the importance that patients place on various symptoms and the effects these symptoms have on the domains of the patients’ quality of life, specifically relating to pain. With the patient and the caregiver placed as the end target of all therapeutic interventions, the combined collaborative efforts of the team are synergistic in their effect. Regular roundtable discussions are a key component of this teamwork (Chasen and Jacobsen, 2013). At times, spiritual counsellors or religious personnel can be of importance. In addition, group educational sessions during which dialogue is encouraged is important to empower participants to play an active role in their own management. Attention to all symptoms including, loss of appetite, loneliness, fatigue and their relationship to pain are all key components that need to be addressed. Social isolation, existential distress, and family disharmony should all be considered an integral cause of pain. The adult ‘Damocles syndrome’, characterized by a state of long-term uncertainty, stress, and anxiety of having disease recurrence, experienced by the patients who have survived cancer and their families must also be considered. Cancer survivors can be physically de-conditioned after the treatments which have caused weight loss, muscle loss (sarcopenia), muscle weakness, and also be psychologically de-conditioned which expresses as a result of a change in body image, a loss of previous role within the family and work spheres, as well as having to face morbidity and mortality. All of these factors contribute to the ‘total pain’ of the patient. Patients with chronic pain are prone to develop ‘maladaptive behaviours’ (McCracken and Eccleston, 2003). These behaviours are manifested by the following cycle. Pain causes diminished activity. This leads to progressive de-conditioning, which gives rise to reduced socialization, altered sleep/awake cycle and medication and drug abuse.

Within the expertise of the various members of the interdisciplinary rehabilitation team, cancer survivors with chronic pain are instructed and trained to build stamina and endurance to counter the muscle de-conditioning, to recognize stressful situations and utilise learned, effective coping strategies. The effect of exercise training and comprehensive health improvement programmes, has been suggested to improve quality of life, particularly in chronic breast or chest-wall pain (Wong et al., 2012). By building on past, successful experiences of the patient, existential meaning can be found and utilized in order to surmount current suffering.

For patients experiencing moderate to severe pain following neck dissection, acupuncture resulted in an improvement of a third of patients on a composite scale. Biogenetics as developed by Shealy, synthesizes techniques of self- regulation with emphasis on positive attitude, a belief in self, relaxation, hypnosis, massage, yoga, and transcutaneous electrical nerve stimulation (TENS), which may help to build strength and stamina (Pujol and Monti, 2007). Psychosocial interventions can include hypnosis, cognitive behavioural therapy, desensitization strategies, guided imagery, and mindfulness-based stress reduction (Keefe et al., 2005).

Pain can be a common experience for many cancer survivors and may develop due to a number of aetiologies. The experience and perception of pain is affected by not only physical but also psychological, cognitive, cultural, and environmental factors, which are specific to each individual. The repercussions of pain which is managed suboptimally can be extensive, and in some cases even lead to increased mortality. Substantial improvements have been made in the outcomes and survival rates of patients with many different types of cancer over the past several years, yet with this the complexity of their pain syndromes continues to increase. Though many cancer survivors can return to relatively satisfactory levels of quality of life, chronic pain can remain a persistent issue for some, and may be underreported and therefore diagnosed and treated suboptimally. It is recognized that cancer survivors experience a greater incidence of comorbidities and psychosocial sequelae. The evidence base is increasing for a number of treatments for cancer survivors to address their pain issues and improve their quality of life. Each cancer survivor is unique and responses to pain management strategies can be diverse. Additional resources should also be focused on equipping patients with the skills to cope with chronic or persistent pain, thereby creating a more efficient transition from active treatment to survivorship. Empowerment of the cancer survivor is a key element of any successful strategy as is collaboration among team members. Respect for survivors’ individuality is also paramount to any successful outcome.

The authors thank Ms Samantha Zinkie for her review and comments.

Complete references for this chapter are available online at <http://www.oxfordmedicine.com>.