Cancer Pain

Approximately 1 in 3 individuals in the developed world will be diagnosed with cancer and half of those patients will die of progressive disease.¹ More than 80% of patients with cancer develop pain before death.² Pain is consistently one of the most feared consequences of cancer for both patients and families. Major improvements in the management of cancer pain in recent years include better assessment of pain, recognition and treatment of opioid-induced neurotoxicity, and the emerging use of opioid rotation and of methadone.

In approximately two thirds of patients with cancer, pain is directly related to the presence of primary or metastatic disease³ ; another third of patients with cancer develop pain syndromes because of treatment, including sequelae of surgery, radiation, or chemotherapy, and other related causes such as osteoporosis, immobility, and infections.³ An understanding of the mechanism of the pain may be helpful in planning for optimal therapy. For example, incidental pain (due to voluntary or involuntary movement) and neuropathic pain (due to central or peripheral nervous system destruction or nerve compression) usually respond poorly to opioid analgesics⁴ and require adjuvant analgesia.

Pain intensity can be assessed accurately by using simple validated methods such as 0 to 10 numerical scales, verbal descriptors, pictorial scales (faces, circles of different colors), or visual analog scales (Figure 1).^{4 - 7} Displaying this information in the patient's chart makes his or her symptom distress visible to caregivers, allowing for better evaluation and monitoring of the quality of care.⁵

The rating of pain intensity by a given patient is not solely a reflection of the level of nociception produced by the painful tumor. The expression of pain intensity should always be considered a multidimensional construct and not a direct representation of somatosensory cortex impact by afferent stimuli (Figure 2). Pain intensity reported by a patient represents the expression of pain that should be used for monitoring and adjusting treatment. Two patients with a similar cancer location may experience different levels of nociception from the tumor itself, different levels of somatosensory cortex activity, and different expression of pain because of the influence of culture, beliefs, mood, or delirium.⁵ Some patients have scores of expressed pain that are consistently high relative to apparent pathophysiology. In these cases, physicians should try to identify which factors are contributing to pain expression.⁵

Patients with cancer pain present with a variety of other symptoms, including fatigue, anorexia, cachexia, chronic nausea, dyspnea, anxiety, and depression. Any of these symptoms can affect the expression of pain and may, in turn, be aggravated by the pain or its treatment.

Cancer pain can be controlled with simple treatments in more than 80% of cases.⁸ In the remaining 20%, it is important to use a multidimensional approach that includes a careful reassessment of the pain syndrome and use of second line agents and/or nonpharmacological interventions.⁸

Mild pain can be treated with acetaminophen or nonsteroidal anti-inflammatory drugs.⁹ Moderate or more intense pain often responds to codeine, hydrocodone, and tramadol, which are mild opioid agonists. Tramadol is also a norepinephrine and selective serotonin reuptake inhibitor and has the advantage of additional nonopioid central effects. A disadvantage of these drugs is that dose escalation potential is very low because of unacceptable toxicity. Partial agonists and opioid agonists/antagonists such as buprenorphine hydrochloride, nalbuphine hydrochloride, or butorphanol are of limited value. They may cause opioid withdrawal when given to patients who have already been exposed to a significant dose of opioid agonists.¹⁰ Meperidine and propoxyphene are best avoided because they can accumulate in patients with decreased renal function or dehydration¹⁰ and cause neurotoxicity. For severe pain, potent opioid agents including morphine (the current criterion standard), hydromorphone, oxycodone, fentanyl, and methadone should be used.

There is little difference in efficacy or adverse effects between these opioid agonists. Patients with cancer pain who have not responded to mild opioids or who have rapidly progressive severe pain at onset should be started on a potent fast-acting opioid, which should be given around the clock; patients should be allowed to take extra doses as needed.¹⁰ Patients with severe pain may need rapid titration of a potent opioid given as a continuous intravenous infusion. In most cases, this approach will control the pain within 24 to 48 hours.

Once patients have achieved good pain control, it is usually possible to maintain analgesia by using slow-release opioids, such as morphine every 12 or 24 hours, oxycodone every 12 hours, or transdermal fentanyl every 3 days. These drugs are easier for patients to use because of reduced frequency of dosing but they are expensive. All patients receiving slow-release opioids should also be given prescriptions for immediate-release opioids that can be used for breakthrough pain.

Approximately 80% of patients with cancer will not be able to take oral opioids for some period before death.¹¹ Patients who already have an intravenous line can be given a continuous infusion of morphine, hydromorphone, fentanyl, or oxycodone, or intermittent injections of methadone. The subcutaneous route, using an indwelling butterfly needle, is simpler, more comfortable, and less expensive and should be used whenever possible.¹¹ Methadone is the only opioid reported to produce irritation when administered subcutaneously.

Patients and families should be educated about the most common adverse effects of opioids to prevent unwarranted fears and noncompliance. Sedation occurs in the majority of patients but there is rapid development of tolerance to this symptom, usually within 3 to 7 days.¹² In less than 10% of patients, the opioid dose required for analgesia causes chronic sedation.¹³ In these patients, a trial of opioid rotation or the use of psychostimulants, such as methylphenidate^{13 - 14} or donepezil,¹⁵ may be useful. In these cases, other therapies should also be considered in order to decrease opioid requirement. Radiation therapy is highly effective in reducing pain, particularly in patients with bone pain.¹⁶ Bisphosphonates can decrease pain intensity as well as bone fractures, hypercalcemia, and the need for radiation therapy in patients with bone metastases.^{17 - 18} In addition, in selected cases in which incidental pain can be anticipated before a planned activity or procedure, such as bathing, dressing, or wound debridement, oral transmucosal fentanyl may provide rapid short-acting analgesia.¹⁹ Nausea will occur in the majority of patients but usually with rapid development of tolerance. Metoclopramide and other promotable agents are effective in the prevention and management of this problem.²⁰

Constipation occurs in the majority of patients receiving opioids and does not improve over time. This symptom is underdiagnosed and can result in serious complications, such as anorexia, vomiting, abdominal pain, and, rarely, abdominal perforation. Contact cathartic laxatives such as senna or danthron, usually combined with stool softeners such as docusate, should be started in all patients receiving regular opioid analgesics, unless there are major contraindications.²¹ Peripherally acting opioid antagonists such as methylnaltrexone are being tested in ongoing clinical trials and may become useful additions to laxatives.²¹

Opioid-induced neurotoxicity ( Article ) is a recently recognized syndrome. It occurs in patients receiving high-dose or prolonged opioid administration and in patients who have decreased renal function or previous borderline cognition. The features of opioid-induced neurotoxicity are mostly excitatory and include delirium, agitation, myoclonus, and hyperalgesia. Hydration, dose reduction, and opioid rotation have been recommended for the management of these symptoms.²²

Sedation

Nausea

Constipation

Respiratory depression

Other (pruritus, anaphylaxis, sweating, urinary retention)

Opioid-induced neurotoxicity: cognitive failure, hallucinations/delirium, myoclonus/grand mal seizures, hyperalgesia/allodynia, severe sedation/coma

Opioid rotation is a treatment approach that has gained acceptance during the past 5 years; it usually involves stopping the initial opioid abruptly and replacing it with an equivalent dose of an alternative opioid.²² Commonly used equianalgesic tables were not developed specifically as guidelines for use with patients receiving chronic high-dose opioid therapy who require opioid rotation.²³ Large interindividual variation in dose ratios will occasionally occur; therefore, in most cases, it is appropriate to begin the new opioid regimen at a daily dose 30% to 50% lower than the equianalgesic recommendation and then slowly increase the dose of the new opioid until adequate analgesia is achieved.

In recent years, methadone has become an attractive analgesic option for opioid rotation.²⁴ This synthetic opioid agonist has excellent oral bioavailability and no known active opioid metabolites. It is also significantly less expensive than other opioids. Its main disadvantages are its long and variable elimination half-life leading to potential accumulation and adverse effects in some patients, and the difficulty in establishing equianalgesic dose ratios during opioid rotation. The dose ratio of most opioids is relatively fixed over a wide range of doses. For example, the morphine/hydromorphone ratio for most patients is approximately 5 (10 mg of morphine = 2 mg of hydromorphone, 100 mg = 20 mg). In the case of methadone, this ratio is highly variable, ranging from less than 5 in patients receiving less than 100 mg of morphine per day to more than 20 in patients receiving more than 1000 mg of morphine per day.^{23 - 25} Once a patient's treatment rotation with methadone has been successful, dose titration and monitoring is the same as with other opioid analgesics. An added advantage of this drug is its availablility as an elixir. The elixir is long-acting and can be administered via tube (eg, in patients with head and neck cancer).

In some patients, opioid titration up to the level of dose-limiting adverse effects does not provide sufficient analgesia.^{5 ,26} Patients with neuropathic pain, which usually has poor opioid responsiveness, may fall into this category. In these cases, adjuvant drugs can provide added pain relief. Adjuvant drugs are agents with no intrinsic analgesic effect that are capable of producing analgesia in certain situations, as when given with opioids. It is important to optimally titrate the opioid analgesic and attempt to manage potential dose-limiting adverse effects such as sedation, nausea, or constipation before starting an adjuvant drug. Anticonvulsants (gabapentin) and antidepressants (desipramine and nortriptyline) are examples of drugs that can be used to enhance analgesia.²⁷ Most adjuvant analgesics are centrally acting agents and may therefore cause sedation, decreased cognition, and fatigue. Corticosteroids can act as effective adjuvant analgesics by reducing peritumoral edema in brain, liver, or thoracic tumors. Antibiotics can be helpful for treatment of sudden increases in pain related to ulceration of head and neck or pelvic tumors.

Patients who have no improvement in their pain intensity after appropriate use of multiple opioid trials, use of adjuvant drugs, and appropriate monitoring of adverse effects may be considered for nonpharmacological interventions. Neurosurgical ablative procedures, such as cordotomy, myelotomy, or thalamotomy, have been available for 40 years. In recent years, augmentative therapies such as intraventricular opioid infusion or deep brain stimulation have been used more frequently.²⁶ Anesthesia procedures that have been tried include the epidural or intraspinal infusion of opioids with or without local anesthetics.²⁷ All of these interventions are complex and expensive, and their role is not currently supported by large randomized controlled trials; however, they can be useful in selected intractable cases.

Cancer pain can be successfully controlled in most patients with a number of safe and relatively inexpensive drugs. In recent years, there have been some advances in our abilities to manage cancer pain. We now recognize that opioids can produce neurotoxicity. We are using methadone more readily and have learned that opioid rotation can help some patients. Physicians can further enhance the well-being of patients with cancer pain if they conduct a careful assessment of the pain syndrome, frequently monitor adverse effects of drugs, and maintain excellent communication with the patient and family.