Palliative Approach to Advanced Illness

Palliative care is the interdisciplinary specialty focusing on improving quality of life for those with serious illness and their families. Over the past decade, palliative care has experienced an expanded evidence base, novel care-delivery models, creative payment mechanisms, and increasing public and professional awareness. Currently, palliative care and hospice have different meanings. Palliative care is interdisciplinary care (medicine, nursing, social work, chaplaincy, and other specialties when appropriate) that focusing on improving quality of life for patients who are living with any serious illness and for their families. Palliative care treats pain, nonpain symptoms, addresses psychological and spiritual distress, and uses advanced communication skills to establish goals of care and help match treatments to patients personal goals. It also provides sophisticated care coordination, thus adding another layer of support to patients, their loved ones, and treating clinicians. Palliative care should be started at the time of diagnosis and is provided concurrently with all other disease-directed or curative treatments. Hospice is viewed as a formal system of interdisciplinary care that provides palliative care services to the dying in the last months of life.

Symptom Management

Many patients with chronic and severe illness experience nonpain symptoms. Nausea affects as many as 70% of patients with advanced cancer and up to 50% of patients with congestive heart failure (CHF), chronic obstructive lung disease (COPD), and renal failure. Delirium occurs in up to 85% of terminally ill cancer patients. Delirium affects not only the quality of life of patients but causes lingering emotional effects on family and caregivers. ^, Fatigue affects two-thirds of patients with advanced CHF, more than 70% of patients with advanced COPD, and 80% of advanced cancer patients receiving chemotherapy and/or radiotherapy. Dyspnea affects up to 90% of patients with end-stage lung disease, 70% of patients with advanced cancer, nearly 50% of patients with end-stage renal disease, and more than 60% of patients with end-stage CHF.

Advanced Directives (Discussion of Code Status, Goals of Care, Advanced Directives, and Care Planning)

As patients near the end of life, communication about goals of care and planning helps assure that patients receive the care they want, alleviates anxiety, and supports families. Effective communication also supports quality of life throughout the illness trajectory, even if death is not an imminent. While goals of care discussions take time, absent, delayed, or inadequate communication about end-of-life preferences leads to poor quality of life, anxiety, family distress, prolongation of the dying process, undesired hospitalizations, patient mistrust of the healthcare system, physician burnout, and high costs. Patients having end-of-life conversations are more likely to know their disease severity, to report less anxiety, and receive less-invasive care. Quality end-of-life conversations lead to better bereavement adjustment for families. Overall, existing evidence does not support the commonly held belief that communication that goals of care and end-of-life issues increase patient anxiety, depression, and/or hopelessness.

Emotional, Psychological, and Spiritual Support

Psychological distress is common in patients with a serious illness and correlates with impaired quality of life. While clinical depression is not a normal part of the dying process, preparatory grief contributes to distress experienced by most dying patients. Preparatory grief occurs as people prepare for death and manifests by mourning impending losses, including loss of function, anticipating missed events (such as a child’s graduation or wedding), and separation from loved ones. Palliative care teams help distinguish between normal preparatory grieving and clinical depression which can be complicated by the neurovegetative symptoms that are part of the severe illness presentation. Palliative care teams help providers identify these differences, allowing for earlier interventions leading to improved symptom control. Palliative care teams also work to improve mood through psychosocial and spiritual support. Palliative care teams also recognize that the management of other symptoms, such as severe pain or intractable nausea, can improve a patient’s mood and quality of life. Many policy-leading organizations advocate the need to integrate physical, psychosocial, and spiritual aspects within palliative care. As patients progress toward the terminal or end-of-life stage, confronting death may prompt a person to engage in spiritual reflection. The palliative care movement has led the way in including the spiritual dimension as a part of total person care defines spirituality as a more comprehensive term than “religiosity.” Spirituality is defined as “a dynamic and intrinsic aspect of humanity through which persons seek ultimate meaning, purpose and transcendence, and experience relationship to self, family, others, community, society, nature, and the significant or sacred. Spirituality is expressed through beliefs, values, traditions, and practices.” Healthcare chaplains typically provide spiritual care, but often, due to insufficient numbers of healthcare chaplains, other members of the palliative care team can help address spiritual concerns. Spiritual care can be given in the manner in which physical care is given, focusing on presence, journeying together, listening, connecting, creating openings, and engaging in reciprocal sharing and common nurturing. Quantitative studies show that 87% of patients consider spirituality to be important in their lives, and between 51% and 77% of patients consider religion to be important. Studies show that spiritual support is associated with better quality of life in seriously ill patients and it is important to identify these needs. An observational study by Winkelman et al. showed that cancer patients with unmet spiritual concerns are more likely to have significantly worse psychological quality of life than those whose spiritual concerns were addressed. A multisite cohort study involving 343 patients with advanced cancer showed that the patients whose spiritual needs were supported received more hospice care and better higher quality-of-life scores. In the same cohort, patients relying on religious faith to cope with cancer were less likely than those with a low level of religious coping to receive mechanical intubation and intensive care unit care near the end of life.

Family and Patient Understanding of Serious Illness

Patient emotions such as anxiety as well as denial are two critical patient-related factors contributing to challenges in discussing serious illness care goals. Anxiety is common in those with serious illness; one-quarter to one-half of all patients with advanced cancer experience significant anxiety symptoms, and 2%–14% have anxiety disorders. Denial of terminal illness is common and can be “healthy” if it facilitates adaptation. Denial that impairs patients’ ability to appreciate reality and engage in an informed manner with key decisions becomes a challenge. Denial is amplified in situations of high anxiety and crisis, such as hospitalization; in these situations, patients lack cognitive and emotional resources to manage strong feelings and difficult decisions, such as those related to end-of-life care. One recent study of patients with either metastatic lung or colorectal cancer, most (69% of those with lung cancer and 81% of those with colon cancer) failed to understand that chemotherapy was noncurative. Clearly, anxiety, denial, and misunderstanding may make it difficult for patients to consider end-of-life care options such as hospice, even when hospice is consistent with the patients’ goals. Data suggest that by engaging in discussions about one’s illness, wishes, benefits, and burdens of disease-modifying therapies, patients achieve better understanding of their illness, which leads to better decision-making about the types of healthcare they wish to receive.

Discharge Planning

Palliative care consultation helps with discharge planning. Palliative care consultants provide critical support through prognostication, symptom management, goals of care clarification, and addressing psychosocial and spiritual concerns. Approaching discharge, hospital-based palliative care teams identify gaps in care occurring during “care transitions” from the hospital to the next care setting, which could be a private home or care facility. Palliative care helps patient and families know whom to call when problems arise. Deficits in these areas are potentially preventable and can be addressed before a patient leaves the hospital. However, they require complex interdisciplinary participation, so responsibility for addressing them is often ambiguous. Studies have shown that many families want to be informed of prognosis and disease progression so that they can prepare emotionally and logistically for a loved one’s death.

Management of Cancer Pain

Pain occurs in 50% of patients with cancer at the time of diagnosis, increasing to 80% of patients with advanced-stage cancer. Pain impacts quality of life, limits function, and affects mood. Untreated pain leads to unwanted outcomes such as requests for physician-assisted suicide or unnecessary visits to the emergency department and hospital admissions. ^, Opioids remain the cornerstone of treatment for moderate to severe pain associated with cancer because they decrease pain and improve function. Strong opioids are recommended for moderate to severe pain associated with cancer. The World Health Organization (WHO) developed a pain ladder, which is a step-by-step approach for the management of chronic pain based on pain intensity. ^,

Epidemiology

Pain occurs at diagnosis in 20%–50% of patients with cancer. Cancer-related pain results from the cancer itself, oncology treatments, and coexisting nonmalignant pain. Cancer types determine pain prevalence; for example, patients with head and neck cancer have the highest prevalence of cancer pain. Age affects cancer pain presentation; younger patients experience more pain and more pain flares than older patients. Of concern is that elderly patients receive less opioids than their younger counterparts. Patients with cancer most commonly experience pain in the back—which should prompt healthcare professionals to exclude spinal cord metastasis—as well as in the abdomen, shoulders, and hips.

World Health Organization Pain Ladder

WHO guidelines form the basis of cancer pain management, using a step-by-step approach to managing cancer pain based on pain intensity. The pain ladder starts with nonopioid analgesics, such as acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs), for mild pain, then adds a so-called weak opioid if pain persists or increases, and then replaces the weak opioid with a Step 3 opioid for severe pain. Some research recommends elimination of Step 2 altogether and starting low dose Step 3 opioids. Morphine remains the first-line opioid to relieve cancer-related pain; however, the evidence level for morphine as a first-line opioid is not strong. Other Step 3 options for moderate to severe pain include methadone, oxycodone, fentanyl, and hydromorphone. These opioids are considered equivalent to morphine. Successfully using the WHO pain ladder helps to provide effective analgesia in 90% of patients in certain settings, although results from randomized control trials show success rates of 70%–80%. ^,

Step 1 Analgesics

Step 1 analgesics include acetaminophen (analgesic only) and NSAIDs (analgesic and antiinflammatory). ^, Dosing of acetaminophen and NSAIDs is limited by a ceiling effect, which means that further dose escalation will not improve analgesia. Acetaminophen dosing is limited by concerns of hepatic toxicity at a total dose of more than 4 g/day. Recent studies suggest no benefit of intravenous acetaminophen on opioid consumption. Acetaminophen works by various postulated mechanisms including central inhibition of the cyclooxygenase system, nitric oxide synthetase, the endocannabinoid system, and the descending serotonin pathways. NSAIDs target and inhibit the enzyme cyclooxygenase, lowering inflammatory prostaglandins which cause nociceptive responses by lowering pain thresholds in nociceptive, neuropathic, and possibly visceral pain through a process called peripheral sensitization. One major action of NSAIDs is the prevention of peripheral sensitization. When considering the use of NSAIDs, choices should be based on experience and the toxicity profile, which depends on the cyclooxygenase 1:2 ratio. There is no ideal NSAID. NSAIDs are orally administered, with the exception of ketorolac, diclofenac, and ibuprofen which are available parenterally. At the end of life, NSAIDs are usually replaced by stronger analgesics in the setting of moderate to severe pain. It may be advisable to continue NSAIDs as long as possible, because clinical trials show additive analgesia when combined with opioids as well as an opioid-sparing effect. Ketorolac is useful for the treatment of cancer pain syndromes not uniformly responsive to opioid therapy. Ketorolac use in the advanced patient with cancer is not recommended beyond 1 week. Oral acetaminophen has not been shown to work synergistically with opioids but has not been shown to be opioid sparing with opioid doses of more than 200 mg of morphine equivalents. NSAIDs treat pain originating in tissues such as connective tissue, joints, serous membranes, and the periosteum; in addition, visceral pain may also respond to NSAIDs.

Step 2 Analgesics

Step 2 on the WHO pain ladder is for mild to moderate cancer pain and includes recommendations for acetaminophen products containing hydrocodone, oxycodone, codeine, and tramadol, as well as propoxyphene and dihydrocodeine (not available in the United States). Propoxyphene is not recommended for use in cancer pain.

Hydrocodone

Hydrocodone is structurally similar to morphine, differing by having a single bond at carbons 7 and 8 and a keto (=O) group at 6-carbon. Hydrocodone is metabolized by both cytochrome P450-dependent oxidative metabolism and glucuronides. CYP3A4 and CYP2D6 generate hydrocodone metabolites: norhydrocodone and hydromorphone, respectively. Polymorphisms of CYP2D6 potentially affect hydrocodone metabolism and therapeutic efficacy. Hydrocodone has equivalent potency as morphine on a milligram-for-milligram basis. Reddy and coworkers found hydrocodone to be more potent than morphine. Rodriguez et al. evaluated 118 study patients with cancer pain and compared hydrocodone/acetaminophen with tramadol in a double-blind, randomized-controlled trial (RCT). A total of 62 study patients received hydrocodone/acetaminophen and 56 received tramadol. Hydrocodone/acetaminophen decreased pain in 57% of participants at a starting dose of 25 mg/2500 mg/day (5 doses per day). Analgesic responses increased by 15% with dose doubling. Pain did not respond to hydrocodone/acetaminophen administration in 29% of study patients. There was no superior analgesic efficacy with the administration of hydrocodone/acetaminophen when compared with patients receiving tramadol in the relief of cancer pain. Another multicenter, double-blind, randomized, parallel-group study compared codeine/acetaminophen phosphate with hydrocodone/acetaminophen for moderate to severe pain. Study patients had chronic moderate to severe cancer pain (>3 on a 10-cm visual analog scale and >1 on a 4-point verbal intensity scale). A total of 88% of study patients had moderate pain and 12% had severe pain; 121 participants received either one tablet of codeine/acetaminophen 30/500 mg or hydrocodone/acetaminophen 5/500 mg orally every 4 h (total daily doses, 150/2500 and 25/2500 mg, respectively) for 23 days. Dose escalation occurred after 1 week if participants experienced severe pain. The primary endpoint was the percentage of study patients achieving a decrease in their pain score by 1 point on a 5-point verbal intensity scale. The secondary endpoint was the percentage of study patients whose pain decreased by at least 3 cm on the 10-point scale. Of the 121 participants, 59 received codeine/acetaminophen and 62 received hydrocodone/acetaminophen. Of the total number of cases, 59 had ages ranging from 60 to 89 years. A total of 58% of patients in the codeine/acetaminophen arm of the study experienced pain relief, and an additional 8% achieved pain relief with a doubling of the dose. Approximately one-third had unresponsive pain. In the hydrocodone/acetaminophen arm of the study, 56% experienced pain relief with a starting dose of 25/2500 mg/day. A total of 15% more achieved pain relief doubling of the initial dose, and one-third of patients did not respond to hydrocodone/acetaminophen. Analgesic efficacy was the same between the two arms of the study.

Tramadol

Tramadol is a synthetic opioid from the aminocyclohexanol group. Tramadol has opioid-agonist properties and prevents the uptake of neurotransmitters norepinephrine and serotonin, making it useful for neuropathic pain. Tramadol has low affinity for opioid receptors, with an affinity to μ receptors 10 times weaker than codeine, and 6000 times weaker than morphine. Tramadol requires conversion to an active metabolite by CYP2D6. This metabolite has affinity for opioid receptors, but less so than Step 3 opioids. Patients who are poor metabolizers of CYP2D6 may experience poor analgesia. Adverse events of tramadol include constipation, dizziness, nausea, sedation, dry mouth, and vomiting. Rodriguez et al. (see above) evaluated 118 participants with chronic cancer pain and compared hydrocodone/acetaminophen and tramadol in a double-blind, RCT. In addition, Wilder-Smith et al. compared tramadol with morphine in a randomized, crossover, double-blind study for severe cancer pain (N = 20). Initially, participants received either tramadol 50 mg or morphine 16 mg every 4 h, with dose titration to achieve pain control. After 4 days, pain intensities did not differ between the groups, although adverse events appeared to differ, with less-intense nausea and constipation noted in the tramadol group. The authors estimated equianalgesic doses of morphine and tramadol and found a ratio of morphine to tramadol of 1:4. Tawfik et al. compared oral tramadol with sustained release morphine for cancer pain in 64 participants with severe cancer pain in a randomized, double-blind study. Tramadol worked best in participants with lesser pain intensity, and morphine worked more effectively and was preferred for participants experiencing severe pain intensity. Good analgesia was achieved in 2 weeks of treatment in 88% of study patients receiving tramadol and 100% of study patients receiving sustained-release morphine. Participants receiving tramadol experienced fatigue (15%), nausea (8%), and sweating (8%). In those receiving morphine, adverse events included constipation (35%), rash (14%), and drowsiness (14%). Bono and Cuffari compared tramadol with buprenorphine in a randomized, crossover trial in study patients with cancer pain. All 60 study patients received either drug for 1 week and then, after a 24-hour wash-out period, were switched to the other drug. The tramadol dose was 300 mg/day and the buprenorphine dose was 0.2 mg 3 times a day. Tramadol was associated with better analgesia ( P < 0.05) and was associated with higher acceptance among study patients. Tramadol was better tolerated than buprenorphine and caused less frequent and milder adverse events, and more study drug withdrawals occurred in the buprenorphine arm.

Codeine

Codeine is a prodrug whose analgesia is mediated through the μ receptor by its metabolite, morphine. A total of 10% of codeine is broken down to morphine by CYP2D6, an enzyme lacking in 5%–10% of white populations. Codeine use is not recommended in the setting of renal failure. One placebo-controlled study has evaluated codeine for cancer pain involving a sustained-release formulation. Thirty study patients with chronic cancer pain completed the study and received either sustained-release codeine every 12 h or placebo in a double-blind study. Crossover occurred after 7 days. Pain intensity was measured using a visual analog scale as well as a 5-point categorical scale. Rescue analgesia (acetaminophen/codeine 300 mg/30 mg every 4 h as needed) was recorded. The median doses of controlled-release codeine doses were 277 ± 77 mg (range, 200–400 mg). Pain intensity scores on a visual analog scale, categorical pain intensity scores when assessed by day of treatment and by time of day, and need for breakthrough pain were significantly lower in the codeine arm ( P < 0.0001).

Step 3 Opioids

The WHO pain ladder recommends Step 3 opioids as first-line therapy for moderate to severe pain (morphine, oxycodone, hydromorphone, fentanyl, levorphanol, methadone, and tapentadol). Step 3 opioids differ from those in Step 2 medications in terms of potency and dosing. Although many Step 2 medications often have a ceiling dose due to fixed formulations with acetaminophen, Step 3 opioids do not have this ceiling allowing dose flexibility. Dosing can increase to achieve adequate analgesia as long as adverse events are tolerated. Step 3 opioids interact with opioid receptors found throughout the central nervous system and peripheral tissues, resulting in analgesic effects, as well potential adverse events, including sedation, respiratory depression, and constipation. Constipation results from opioid receptor activation in the intestinal tract leading to decreased bowel motility and interference with peristalsis. Varying degrees of activation and affinity for each receptor subtype may account for the differences in efficacy and activity between opioids. In addition, interindividual variation is significant in analgesic response and toxicities based on genetic disparities.

However, a reliable method to predict an individual patient’s response does not exist and a paucity of evidence suggests superiority of one opioid over another in terms of efficacy or tolerability.

Morphine

WHO considers morphine the drug of choice for moderate to severe cancer pain. Morphine is glucoronidated in the liver. There is a small contribution (30%) to glucuronidation from the kidneys. First-pass metabolism of oral morphine determines its systemic bioavailability which is 25%. Morphine has three major metabolites: normorphine, morphine-3-glucuronide, and morphine-6-glucuronide. Metabolites are principally eliminated by the kidney and accumulate in renal failure contributing to adverse effects. The elimination half-life of morphine is approximately 2 h and is independent of route of administration or formulation. Morphine administered by sublingual and buccal routes has a delayed onset of action compared with oral morphine (smaller peak plasma levels, lower bioavailability, and larger interpatient variability). Intrathecal morphine is 100 times as potent as its oral form, and epidural morphine is 10 times as potent (0.5 mg intrathecally equals 5 mg epidurally). Morphine dosing is minimally affected by hepatic failure but is greatly affected by renal failure. A linear relationship exists between creatinine clearance and renal clearance of morphine and metabolites morphine-3-glucuronide, and morphine-6-glucuronide. Kidney failure impairs glucuronide excretion more than morphine excretion, increasing the duration of action of morphine-6-glucuronide and morphine-3-glucuronide, thus leading to adverse events such as sedation and/or myoclonus. Glucuronidation is largely unaffected by cirrhosis. Morphine should be avoided when creatinine clearance is less than 30 mL /min. Morphine continues to be considered the standard medication for the treatment of cancer pain partly due to familiarity with the product as well as cost. However, it may not always be the ideal product due to issues associated with its metabolism and adverse-event profile. Almost all randomized controlled comparisons of potent opioids show equivalence (i.e., noninferiority) to morphine.

Methadone

Methadone is unique in that it works at three levels to provide analgesia. It is a potent opioid with strong interactions with the μ opioid receptor, it is an N-methyl- d -aspartate (NMDA) receptor antagonist, which is activated in chronic pain, and when blocked, enhances analgesia and reverses opioid tolerance. Methadone inhibits the uptake of neurotransmitters, such as norepinephrine and serotonin, which play a role in descending pain modulation. Methadone is a second-line analgesic for pain poorly responsive to other opioids. It shows promise as a first-line analgesic for cancer pain, neuropathic pain, and as a breakthrough agent. Methadone is available in oral, sublingual, and intravenous formulations. Methadone has different pharmacokinetics from other opioids. Methadone has a long half-life that varies between 60 and 120 h. High-dose intravenous methadone is associated with QT prolongation and torsades de pointes. The risk for QT prolongation is less with oral methadone. A retrospective study found that oral methadone can cause QT prolongation in 16% of patients. Dosing of methadone is complicated. Methadone shows an inverse relationship of its starting dose to the total morphine equivalent daily dose (MEDD). As the MEDD increases, the equianalgesic dose of methadone progressively decreases. Clinical trials comparing methadone to morphine have not shown superiority of methadone; in fact, three studies have compared morphine and methadone as first-line therapy for cancer-related pain. ^{, ,} Ventafridda et al. Reinhart compared methadone with morphine for moderate to severe cancer pain in 54 study patients who had previously been taking Step 2 opioids. Patients received either morphine or methadone by mouth for 14 days. While both therapies provided clear reductions in pain intensity, analgesia was less stable in the morphine arm, and study patients receiving morphine had a higher incidence of dry mouth. Otherwise, no other differences in toxicities or the ability to achieve pain relief were seen. Mercadante et al. conducted a prospective randomized study in 40 study patients with advanced cancer who required strong opioids for their pain management and receiving home hospice care. Study patients were treated with sustained-release morphine or methadone in doses titrated to pain relief and administered two or three times daily according to clinical need. Results suggested that methadone achieved analgesia more rapidly and that methadone analgesia was more stable than that achieved with morphine. Bruera and coworkers compared the effectiveness and adverse events of methadone and morphine as first-line treatment with opioids for cancer pain. In this multicenter, international study, 103 participants with pain requiring strong opioids were randomly assigned to receive either methadone or morphine for 4 weeks. Participants having a 20% or more reduction in pain scores were equal in both groups. Patients in both arms reported satisfaction with their therapies. The methadone arm had a higher number of dropouts and required fewer dose adjustments to achieve analgesia than those in the morphine arm.

Hydromorphone

Hydromorphone is similar in structure to morphine and is available as parenteral and oral products. It is the best opioid for subcutaneous administration. The oral formulation is available in an immediate-release formulation, and a single, daily dose, extended-release formulation has been shown to be effective in patients with cancer. ^, Administered orally, hydromorphone has a bioavailability of 50% and its plasma elimination half-life is 2.5 h. Metabolism in the liver produces hydromorphone-3-glucuronide, which has no analgesic properties but can cause neurotoxicity. Hydromorphone is effective in treating pain in patients with renal impairment. Hydromorphone metabolites accumulate in patients receiving chronic infusions. ^, A double-blind, randomized comparison of sustained-release hydromorphone with sustained-release morphine showed equivalence in pain relief. Systematic reviews involving 11 studies and 645 study patients show that hydromorphone equals morphine in analgesic effect. More recent systematic reviews confirm equivalency.

Oxycodone

Oxycodone is available as immediate-release and sustained-release formulations. (Intravenous formulations are available in Europe.) The immediate-release formulation has a half-life of approximately 2–4 h and a bioavailability of 50%–60%. The primary difference between oxycodone and morphine is its bioavailability: its half-life is longer than normal in renal failure and liver failure. Oxycodone is metabolized to noroxycodone and oxymorphone via CYP 2D6. Multiple studies show therapeutic equivalency with morphine for cancer pain. ^{, ,} Minor differences in adverse events have been described. Hallucinations and nausea are less common with oxycodone treatment. ^, However,because of its cost and lack of versatility, morphine remains the preferred analgesic. ^, Bruera et al. demonstrated that oxycodone is 1.5 times as potent as morphine when comparing analgesic potency.

Oxymorphone

Oxymorphone is a semisynthetic μ opioid agonist 1.2 times as potent as morphine. Until recently, oxymorphone was available as parenteral injection and in suppository form; however, immediate-release and long-acting oral formulations were developed that make oxymorphone another option for treating moderate to severe pain. Trials in malignant and nonmalignant pain confirm its potential as another Step 3 option. Oxymorphone is more lipid soluble than morphine. The oral bioavailability of oxymorphone is approximately 10%, which is the lowest of the oral Step 3 opioids. In healthy volunteers, the half-life ranges from 7.2 to 9.4 h. The half-life of immediate-release oxymorphone is longer than that of morphine, hydromorphone, and oxycodone. Immediate-release oxymorphone tablets may be given at 6-hour intervals, whereas the extended-release formula is dosed twice daily. Steady-state conditions are achieved after 3–4 days. Oxymorphone is subject to hepatic first-pass effects and is excreted by the kidneys. Oxymorphone accumulates in renal failure. Oxymorphone has a prolonged half-life in renal failure. In the setting of hepatic insufficiency, increasing the dosing interval is recommended. Sloan et al. conducted a pilot study comparing extended-release oxymorphone and controlled-release oxycodone in 86 study patients with moderate to severe cancer pain. The tolerability and safety profiles (e.g., nausea, drowsiness, somnolence) were similar between the two drugs, and no significant differences in daily pain intensity scores were seen between extended-release oxymorphone and oxycodone.

Fentanyl

Fentanyl, a lipid-soluble, synthetic opioid, is available as parenteral, transdermal, and transmucosal products. Its lipophilic properties allow it to cross both the skin and oral mucosa.

The transdermal formulation delivers fentanyl from the reservoir into the stratum corneum where it then slowly diffuses into the blood. Another formulation on the market is a matrix-delivery system in which fentanyl is dissolved in a polyacrylate adhesive. This formulation can be cut. Both the reservoir and matrix-based patches have similar kinetics and clinical effectiveness. Fentanyl is metabolized to norfentanyl under the influence of CYP3A4. The concomitant use of fentanyl with potent CYP3A4 inhibitors (e.g., ritonavir, ketoconazole) may affect its metabolism. Fentanyl is safe to use in patients with renal failure. Absorption of transdermal fentanyl may be impaired in cachectic patients. The elimination half-life of transdermal fentanyl is approximately 12 h. Conversions to fentanyl are made by calculating the MEDD and the using the ratio of 2 mg:1 μg to reach the starting fentanyl dose. Most experts do not recommend using transdermal fentanyl for acute titration. ^, Compared with morphine, constipation is less frequent with fentanyl. Comparisons between morphine and transdermal fentanyl have shown equal analgesic efficacy. When compared with morphine, daytime drowsiness and interference with daytime activity occur at lower rates. ^, The oral transmucosal administration of fentanyl has been extensively explored. In one study, 25% of the delivered drug was transmucosally absorbed, with another 25% delivered through the gastrointestinal tract. RCTs of oral transmucosal fentanyl citrate show increased analgesic efficacy and patient preference over placebo and morphine. Administration of fentanyl is being explored through other routes (e.g., intranasal). Rapid intravenous administration of fentanyl in the emergency department can result in rapid improvement in pain control.

Buprenorphine is emerging as another option for cancer pain. Well known as a strong analgesic, the development of a transdermal formulation makes it a possible option for cancer pain. Buprenorphine is also available in intravenous and sublingual formulations, with the sublingual formulation having a bioavailability of 50%–65% and a half-life of more than 24 h. After application of the transdermal formulation, plasma concentrations steadily increase. The larger-dose transdermal formulations achieve the minimum effective therapeutic dose sooner. Open-label, randomized, parallel-group, multiple dose pharmacokinetic studies show that the minimum effective concentrations are reached after 31, 14, and 13 h, respectively, with the 35, 52.5, and 70 mg/h patches (not available in the United States). Patches reach steady state after the third consecutive application. Bioavailability of the transdermal formulation is 60% compared with the intravenous route. Effective plasma levels occur within 12–24 h and last for 72 h. It takes 60 h to reach Cmax. After patch removal, concentrations decrease to one-half in 12 h, then more gradually decline. Metabolism by CYP3A4 and CYP2C8 converts buprenorphine to an active metabolite, norbuprenorphine, which is a weaker but full-opioid agonist. Buprenorphine and its metabolite later experience glucuronidation. Liver disease affects buprenorphine metabolism. With involvement of both cytochrome oxidase system and glucuronidation in metabolism, severe liver disease potentially inhibits formation of norbuprenorphine through effects on the cytochrome oxidase system. Liver disease does not affect glucuronidation as much. Buprenorphine is safe to use in the presence of mild to moderate liver failure as well as in the setting of renal insufficiency and dialysis. Buprenorphine produces adverse events similar to other Step 3 opioids and include constipation, urinary retention, sedation, and cognitive dysfunction. Buprenorphine causes less nausea than transdermal fentanyl. Three Phase 3 placebo-controlled studies confirmed the efficacy of transdermal buprenorphine for cancer pain and also demonstrated the absence of a dose ceiling and opioid antagonist activity.

Levorphanol

Levorphanol is a potent Step 3 opioid with similarities to methadone. Structurally similar to morphine, levorphanol has strong affinity for μ, δ, and κ opioid receptors. Levorphanol is also a noncompetitive NMDA receptor antagonist and blocks NMDA with the same potency as ketamine. Levorphanol can be orally, intravenously, subcutaneously, and intramuscularly administered. ^, Levorphanol has poor absorption via the sublingual route compared with other opioids such as morphine sulfate (18%), buprenorphine (55%), fentanyl (51%), and methadone (34%). The pharmacokinetics of levorphanol are similar to methadone with a duration of analgesia ranging from 6 to 15 h and a half-life as long as 30 h. First-pass metabolism produces a 3-glucuronide metabolite, which may have neurotoxicity. Metabolites of levorphanol are renally excreted. The high volume of distribution and increased protein binding suggest that levorphanol should not be dialyzable. The predominant mode of metabolism is hepatic. In the setting of hepatic insufficiency, it is advisable to consider an increased dosing interval. Experience and clinical trial results suggest that the type and incidence of adverse events are similar to those seen with strong opioids. Levorphanol has been studied as a treatment for chronic neuropathic pain and has been shown to be effective.

Tapentadol

Tapentadol is structurally related to tramadol. Opioid receptor-binding studies show that tapentadol is a strong opioid with high-affinity binding to μ, δ, and κ opioid receptors. In human μ opioid receptor S GTPγS-binding assays, tapentadol shows agonistic activity, with an efficacy of 88% relative to morphine; tapentadol also targets neurotransmitters such as norepinephrine. It provides potent inhibition of norepinephrine uptake. Tmax is achieved in 1.25–1.5 h, the half-life is 24 h, and the plasma protein binding is 20%. Tapentadol metabolism is mainly by glucuronidation, with some contribution from CYP enzymes, especially CYP2D6. Tapentadol has no active metabolites. Excretion is predominantly renal. Tapentadol causes adverse events such as nausea, dizziness, vomiting, headache, and somnolence. Tapentadol has less effect of the gastrointestinal tract than other Step 3 opioids.

The manufacturer recommends against using tapentadol in severe hepatic or renal failure, and dosing above 600 mg/day should be avoided. Equianalgesic dosing studies are unavailable but information from its use in non-cancer-related pain studies suggests morphine 60 mg is equivalent to tapentadol 100–200 mg. The current dosing recommendations is 50, 75, or 100 mg every 4–6 h. Tapentadol does not affect the QTc interval. Prolonged-release tapentadol (100–250 mg twice daily) is effective compared with placebo for managing moderate to severe, chronic, malignant tumor-related pain.

Interventional Pain Modalities

Clinicians consider “Step 4” of the WHO pain ladder when they encounter an inadequate response to Step 3 agents, adjuvants, or both. Treatment options include use of nerve blocks, and/or spinal administration of local anesthetics, opioids, and other adjuvants. Abdominal pain may be controlled by a blockade of the celiac plexus, which, if successful, can block nociceptive input from many structures in the upper abdomen, in particular the pancreas. Use of the superior hypogastric ganglion block for the treatment of malignant pelvic pain was first described by Plancarte et al.

Opioids

Opioid Responsiveness

Opioid responsiveness is the degree of analgesia achieved as the opioid dose is titrated to an endpoint, defined either by intolerable side effects or the occurrence of acceptable analgesia. Pain poorly responsive to opioids exists when intolerable adverse events, inadequate analgesia, or both continue during opioid escalation. Pharmacodynamic and nonpharmacodynamic factors affect opioid responsiveness. Identifying pain poorly responsive to opioids should lead the healthcare professional to consider the use of adjuvant analgesics, opioid switching, changing the route of administration, using NMDA antagonists, or interventional pain techniques.

Routes of Administration

Opioids are available in many dosage forms and routes of administration including via the oral, rectal, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, and intraspinal routes of administration. Oral administration is simple, cost-effective, and is the preferred route of delivery. Both immediate-release and extended-release preparations are available. Clinicians use the subcutaneous, intravenous, rectal, transdermal, transmucosal, and intraspinal routes when patients cannot take oral medications. Intramuscular administration is contraindicated as it does not confer any pharmacokinetic advantages and is painful. Subcutaneous delivery is easy, effective, and safe. Intravenous routes are useful when pain is severe or pain levels have acutely increased. Transdermal fentanyl preparations are effective for patients unable to take oral medications and have stable pain control. Other short-acting opioids are used to control pain when transdermal fentanyl is initiated, because levels of fentanyl gradually increase during a 12- to 24-hour period until reaching steady state. Transmucosal fentanyl is similar to intravenous administration in its rapid onset, and it can be used for acute breakthrough pain. Historically, dosing of transmucosal fentanyl was not thought to be based on dose proportionality, but this consideration has been challenged. Intraspinal administration of opioids can either be epidural or intrathecal. This method is the most invasive technique and requires a specialist for initiation. This delivery confers advantages in patients with significant dose-limiting adverse events as systemic involvement is circumvented. Intraspinal delivery allows the addition of adjuvant medications to opioids that can be directly administered to the spinal cord.

Dose Titration

Clinicians adjust opioid analgesics to balance adequate pain control and adverse events. Dosage requirements change with cancer progression. Most patients with cancer have chronic daily pain, so analgesics should be given on a scheduled basis. Breakthrough analgesics are ideally given according to the time it takes to reach Cmax. The Cmax depends on the route of administration. Cmax is 1 h for the oral route, 30 min for the subcutaneous route, and 6 min for the intravenous route. ^, Once Cmax is reached, another dose should be given if pain is not adequately controlled. Multiple approaches to opioid initiation and titration exist. The European Association for Palliative Care recommends dose titration with immediate-release oral morphine every 4 h, with breakthrough dosing of the same dose given every hour as needed. The scheduled dose should then be adjusted to account for the oral MEDD. Several studies have shown acceptable pain control and adverse event profiles with use of 5 mg every 4 h in study patients naive to opioids and 10 mg every 4 h in patients previously using a Step 2 drug. ^, After acceptable pain control occurs, patients can use extended-release preparations as this is convenient and improves compliance. Breakthrough dosing is 10%–20% of the MEDD. Opioid titration with sustained-release formulations is slower than titration with immediate-release formulations. Titration with intravenous medications is effective and tolerated. In patients on established opioid regimens, dosing adjustment should be made according to the level of pain. Adult cancer pain guidelines recommend an increase of 25%–50% in the total MEDD for moderate pain (4–6 out of 10) and 50%–100% for severe pain (7–10 out of 10).

Equianalgesic Conversions

When converting between opioids, equianalgesic guidelines are followed although they may be modified according to clinical judgment with regard to adequacy of a patient’s current pain medication regimen. Opioid rotation may be due to poor analgesia, excessive adverse events, convenience, or patient preference. Incomplete cross tolerance is identified when patients may develop less of a response (e.g., poor analgesia, adverse events) to a particular opioid over time. Patients may not show these characteristics with a new opioid, despite similar action between opioids, and slight variations in opioid structures may account for this. Patients may not show these characteristics with a new opioid, despite similar action between opioids, or slight variations in opioid structures. When calculating the dose of the new opioid, new doses should be reduced by 25%–50% to account for non-cross tolerance especially when current pain is controlled. This is not done for fentanyl or methadone.

Adverse Events

The development of adverse events varies between individuals and depends on factors such as age, comorbidities, stage of illness, and genetic differences. Impaired renal function increases the risk of adverse events due to accumulation of active metabolites. The most common adverse events include constipation, nausea, vomiting, and altered cognition. Other adverse events may include xerostomia, urinary retention, respiratory depression, myoclonus, pruritus, and hyperalgesia. Most adverse events from opioid use subside within days to weeks, except for constipation for which patients do not develop tolerance and is not dose related. For those symptoms that persist or are present during the initiation of opioid therapy, symptom management is a key element of care. Constipation is prophylactically managed. Opioids inhibit gastrointestinal peristalsis; thus, all patients should receive a stimulant laxative such as senna. Bowel stimulant dose is typically increased as the opioid dose is increased. Dietary recommendations, such as increasing fiber in the diet, are unrealistic in patients with advanced disease because hydration is necessary to facilitate the action of fiber, often something difficult to achieve in ill patients. Constipation is exacerbated by metabolic abnormalities, including diabetes, hypercalcemia, hypokalemia, and hypothyroidism, that should be corrected if possible. Increased physical activity is often helpful if possible. Use of quaternary opioid antagonists may be needed. The quaternary agents do not cross the blood-brain barrier and do not reverse the analgesic effects of opioids.

Nausea frequently occurs at the start of opioid therapy but seldom persists. Ongoing nausea may occur with advanced disease or as a complication of disease treatments. Opioids can cause nausea through several mechanisms, through direct stimulation of the chemoreceptor trigger zone, increased sensitivity of the vestibular apparatus, or delayed gastric emptying. Management consists of therapies targeting these processes. Dopamine antagonists, such as prochlorperazine or haloperidol, work on the chemoreceptor trigger zone. Antihistamines or anticholinergics can be used in patients who have nausea associated with movement. Metoclopramide is both a dopamine antagonist and promotility agent commonly used for the treatment of nausea in palliative care. Ondansetron, a serotonin receptor antagonist, is also a first-line agent for the management of nausea. If sedation and altered sensorium are present, then management should include evaluation for other sources such as dehydration, drug interactions, or disease progression. Studies have investigated use of stimulants such as methylphenidate and modafinil with varying results. ^, If excessive adverse events limit pain control or impair quality of life, opioid rotation is often effective at achieving greater pain control with less adverse events. In addition, this method of adverse-event management is preferable in patients for whom polypharmacy is a concern. Based on pharmacodynamics studies, dose-response relationships exist for central nervous system effects, such as sedation, myoclonus, and delirium, and may improve with dose reduction.

Treating Neuropathic Pain

Although adjuvant analgesics are often used in neuropathic pain, healthcare professionals should consider opioids as another option for neuropathic pain. Opioids are recommended as part of neuropathic pain algorithms.

Adjuvant Analgesics

Adjuvant analgesics are drugs with a primary indication other than pain that have analgesic properties. The group includes drugs such as antidepressants, anticonvulsants, corticosteroids, neuroleptics, and other drugs with narrower adjuvant functions. Adjuvant analgesics are particularly useful when evidence of decreased opioid responsiveness is present.

Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors

The tricyclic antidepressants have been studied for use in neuropathic pain syndromes, although study results are conflicting about their analgesic effectiveness. Amitriptyline has been shown to decrease chemotherapy-induced neuropathic pain intensity and improvement in quality of life with 10 mg per day up to 50 mg per day for 8 weeks. Side effects of drowsiness, confusion, orthostatic hypotension, and dry mouth may limit the use of this drug especially in the elderly. ^, A Cochrane review in 2015 of nortriptyline for neuropathic pain in adults included six studies treating 310 patients from a range of 3–8 weeks found little evidence to support its use for neuropathic pain. Additionally, tricyclic antidepressants should also be cautiously used in patients with coronary artery disease or cardiac rhythm disorders, as well as those with a history of narrow-angle glaucoma and urinary retention. The anticholinergic properties of these drugs contribute to delirium in the elderly or anyone at risk for delirium such as patients whose cancer has metastasized to the central nervous system. These drugs should be started at the lowest dose with cautious escalation. Dose escalations are made every 3–4 days if analgesic response is suboptimal. Selective serotonin reuptake inhibitors have a limited role as adjuvants, although paroxetine and citalopram have been evaluated for nonmalignant neuropathic pain. ^, No studies have been performed on cancer pain.

Serotonin and Norepinephrine Dual Reuptake Inhibitors

Newer drugs, such as duloxetine, inhibit the uptake of both serotonin and norepinephrine, both considered key neurotransmitters that suppress painful transmission of peripheral pain stimuli to the dorsal horn of the spinal cord. Smith and colleagues conducted a randomized, double-blind, placebo-controlled crossover trial at eight National Cancer Institute (NCI)-funded cooperative research networks enrolling 231 patients receiving primarily paclitaxel and oxaliplatin. Patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. After 5 weeks of duloxetine (1 week of duloxetine 30 mg and 4 weeks of 60 mg) compared with placebo, patients who received duloxetine had an increased reduction in pain (59% of those initially receiving duloxetine vs. 38% of those initially receiving placebo reported decreased pain of any amount). The drug was considered safe and well tolerated with fatigue, insomnia, and nausea being the most common adverse effects. Duloxetine seems to work better on patients receiving oxaliplatin. Venlafaxine also inhibits the uptake of serotonin and norepinephrine and is effective for painful neuropathy and neuropathic pain associated with therapy used in breast cancer. It has been found to relieve painful polyneuropathy with as much effectiveness as imipramine.

Dopamine and Norepinephrine Uptake Inhibitors

Bupropion is a second-generation nontricyclic “atypical” antidepressant that is a specific inhibitor of neuronal noradrenaline reuptake and a weak inhibitor of dopamine reuptake at presynaptic level. It does not affect sodium or calcium channels. Importantly, it does not block histaminergic, alpha-adrenergic, and muscarinic receptors and thus is well tolerated in patients who are having difficulty with tricyclic antidepressants. Bupropion can potentiate seizure activity and is contraindicated in patients with a history of seizures, eating disorder, or abrupt alcohol cessation. Currently, bupropion is indicated for depression, seasonal affective disorder, and smoking cessation. There seems to be evidence in favor of bupropion in neuropathic pain. Semenchuk conducted an open-label pilot study to assess the efficacy of bupropion SR on neuropathic pain. In this study, 22 patients with diagnosis of neuropathic pain underwent treatment with bupropion SR 150 mg once a day for 7 days followed by 150 mg bupropion SR twice a day for 7 weeks. A total of 15 patients (68%) reported significantly decreased symptoms after bupropion therapy. Adverse effects were mild including insomnia, tremor, gastrointestinal upset, and weakness/dizziness. None of the patients dropped out because of adverse effects. A subsequent 12-week, randomized, placebo-controlled, double-blinded, crossover study showed that of the 41 patients who started the study, 30 (73%) reported “improved” or “much improved” pain after 6 weeks of bupropion SR therapy. The mean average pain score at baseline was 5.7, which dropped to 4.0 on bupropion but remained unchanged on placebo. Adverse effects were minimal and quality of life improved.

Corticosteroids

Corticosteroids are used to treat bone pain and swelling in the brain and spinal cord due to metastatic disease. Their role as antiinflammatory drugs as a result of reducing proinflammatory cytokines, stimulating lipocortin synthesis, and inhibiting collagenase expression makes them powerful for pain resulting from inflammation such as nerve root inflammation. They are often considered for painful liver metastasis and obstruction of the ureter, although the evidence base for this use is not strong. The most commonly used corticosteroid is dexamethasone, due to its low mineralocorticoid properties resulting in less fluid retention. It is metabolized by the CYP3A4 hepatic enzyme, has many drug interactions, and its effect may be altered by CYP3A4 inhibitors and inducers. Its effects on cancer-induced fatigue, cachexia, nausea, vomiting, and depression provides additional benefits. Optimal dosing for palliation may be 8 mg/day as this dose has no more adverse events than placebo. In the case of spinal cord compression, recommendations exist for either high-dose (96 mg/day) or low-dose (16 mg/day) dexamethasone. Higher doses and longer use of steroids increases the occurrence of adverse events. The management of edema associated with brain metastasis can be treated with dexamethasone 4–6 mg every 6 h with a careful taper during the last phases of palliative radiation therapy. The minimal effective dose for brain metastasis is 8 mg/day. Steroids can be useful to counteract the phenomenon of radiation “flare,” which occurs during radiation therapy to painful bony sites.

Anticonvulsant Drugs

Anticonvulsants can be used for managing neuropathic pain. The most often used anticonvulsant for neuropathic pain is gabapentin, which is effective for cancer-related neuropathic pain. ^, It is an inhibitor of the alpha-2-delta-1 calcium channel subunit that blocks neurotransmitter release resulting in decreased nociception in neuropathic pain. Gabapentin can have significant adverse events if it is started at too high a dose or titrated too fast. Dosing begins at 150 –300 mg at bedtime, with escalations every 3 days if pain control is suboptimal. The chief adverse event is somnolence. Gabapentin must be dose adjusted for renal insufficiency, with the maximum dose for normal renal function of 3600 mg/day. A Phase 3 randomized, double-blind, placebo-controlled, crossover trial by Rao and colleagues found no significant benefit to using gabapentin at 2700 mg per day for 6 weeks for symptoms due to chemotherapy-induced peripheral neuropathy. Another anticonvulsant that may be useful for cancer pain is phenytoin. Agents such as lamotrigine, oxcarbazepine, pregabalin, topiramate, and levetiracetam have been used for nonmalignant neuropathic pain and are considerations in the refractory case, but they have not been studied in the cancer pain population. Levetiracetam requires further study for cancer-related neuropathy. Lamotrigine is not effective in chemotherapy-related neuropathy.

Oral and Parenteral and Transdermal Anesthetics

The parenteral anesthetic commonly used for refractory cancer pain is lidocaine. While there is limited data on its use, some studies suggest its efficacy in opioid-refractory cases of cancer pain. There is less evidence supporting the benefit of lidocaine for neuropathic pain. ^, One study in patients with cancer with refractory pain showed improved analgesia with a single dose of lidocaine. The recommended starting dose is 1–5 mg/kg infused for 20–30 min. In patients who are frail, lower doses may be needed. Lidocaine should be avoided in patients with coronary artery disease. One potential benefit of lidocaine is prolonged pain relief that occurs following its infusion Lidocaine can be given in the home or hospice setting. Cognitive impairment, delirium, dizziness, perioral numbness, and somnolence are adverse effects to be aware of. Mexiletine, an oral congener of lidocaine, has been used after lidocaine infusions. Clinical trial results suggest that mexiletine has a distinct adverse-event profile and may not be tolerated by all patients.

Transdermal Local Analgesics

Transdermal lidocaine (5% patch) provides another route for local anesthetics. It can be used to treat post herpetic neuralgia, but its role in cancer-related neuropathy requires further study. A study by Garzon-Rodriguez and colleagues found that it can be a helpful short-term treatment option for painful scars such as postthoracotomy or postmastectomy, and pain from chest wall tumors. ^, The patch has minimal systemic absorption, and it can be applied 12 h per day; evidence suggests that increasing the number of patches and extended dosing periods may be safe. ^, It may take several weeks to observe a maximal effect. The most frequently reported adverse events are mild to moderate skin redness, rash, and irritation at the patch application site.

Ketamine

Chronic pain is associated with central nervous system changes, including activation of the NMDA receptor, leading to the development of decreased opioid responsiveness. Pharmacological blockade of the NMDA receptor offers a therapeutic approach in the setting of decreased opioid responsiveness. As an NMDA receptor antagonist, ketamine has been considered in the management of refractory cancer pain and may lead to reduced opioid requirements. ^, It is recommended by the WHO for the management of refractory pain. Given at subanesthetic doses (<1 mg/kg), ketamine is an effective analgesic in cancer-related neuropathic pain. Multiple routes exist for administration including oral, intravenous, subcutaneous, and topical routes. It is metabolized via CYP3A4 and no significant drug interactions have been reported. Adverse effects to be aware of are hallucinations, psychomimetic toxicity that improve with haloperidol and diazepam, hypertension, nausea, and vomiting. ^{, ,} Its analgesic effect is due to the norketamine metabolite, which has a duration of action of 8 h, and pharmacologically, no major differences exist in the characteristics between the isomers. ^, Ketamine has protein binding of 20%–30%. Its oral bioavailability is 17%, it has an onset of action of 15–20 min, and it has a half-life of 2.5–3 h. Its intravenous onset of action is within seconds and, subcutaneously, the onset of action is 15–20 min. The half-life is 2–3 h for both routes. The results of one trial of subcutaneous ketamine as an add-on option to opioids showed no efficacy in cancer-related nociceptive pain and a Cochrane review found insufficient evidence regarding the use of ketamine as an opioid adjunct for cancer pain relief ; however, a recent study by Cheung and colleagues found a favorable response to ketamine in patients using one or more opioid analgesics.

Cannabinoids

Formulations of cannabinoids, the cannabinoid extracts, have been studied for cancer-related pain. Two RCTs have studied tetrahydrocannabinol (THC)/cannabidiol (CBD) and found significant change in pain compared with placebo and a decrease in breakthrough pain medications. ^, A third RCT found no significant difference compared with placebo for chronic neuropathic pain related to taxol-based chemotherapy. The cannabinoid used in these studies is nabiximols, which is an extract that contains THC 2.7 mg and CBD 2.5 mg per dose. It is formulated in ethanol/propylene glycol with peppermint flavoring and is designed as a pump spray for self-administration and titration via the oromucosal route. Another larger study using the same formulation again confirmed this cannabinoid extract as an add-on therapy for advanced cancer. Pain relief with THC has been shown to be dose dependent and one study found a dose of 20 mg to provide significant relief (Noyes). Significant adverse effects include mental clouding, drowsiness, euphoria, somnolence, and nausea.

Neuroleptics

Second-generation (atypical) antipsychotics, such as olanzapine, have been shown to have antinociceptive activity in animal models. Khojainova et al. evaluated the analgesic activity of olanzapine in eight study patients with severe cancer pain unresponsive to increased opioid dosing and who were receiving olanzapine for the treatment of severe anxiety and mild cognitive impairment. Patients reported a decrease in pain scores. The authors note that this decrease may be the result of intrinsic analgesic action but may also be the result of treated anxiety and improved cognitive function. Further studies are needed to explore olanzapine’s analgesic potential.

Agents Specifically Used for Bone Pain

Bone pain is a common problem in the palliative care setting. Radiation therapy can be effective with localized pain. Systemic therapies with NSAIDs, corticosteroids, bisphosphonates, and radiopharmaceuticals can be useful for patients with multifocal lesions.

Bisphosphonates

Bisphosphonates are analogues of inorganic pyrophosphate that inhibit osteoclast activity and can be useful in many types of cancer in which bone resorption leads to complications. Bisphosphonates bind to calcium on bone, become ingested by osteoclasts, and subsequently kill osteoclasts thus preventing bone resorption. The end result of decreased osteoclast activity is increased bone stability and reduced pathological fractures. In the United States, zoledronic acid and pamidronate are used. The most potent bisphosphonate is zoledronic acid, which has been shown to reduce pain and prevent the occurrence of skeletal-related events in breast cancer, prostate cancers, multiple myeloma, and a variety of solid tumors, including lung cancer. Breast cancer and multiple myeloma are the most responsive to bisphosphonates. Denosumab is useful when renal insufficiency precludes the use of bisphosphonates. Pain reduction occurs as soon as within a week and can last up to 3 months with redosing every 3–4 weeks for maximum effect. The most common adverse effect is a flu-like syndrome.

Radiopharmaceuticals

Radionuclides are agents absorbed in areas of metastatic cancer activity. Strontium-89, radium-223, and samarium-153 are effective for diffuse bony metastatic disease (without visceral disease) that bind to areas with rapid bone turnover such as osteoblastic metastases such as in the case of prostate cancer. Pain relief often occurs within 1–2 weeks and may last from 2 to 6 months. Radium-223 has been found to increase survival by 3 months in patients with metastatic prostate cancer with less myelosuppression and adverse effects. This treatment is appropriate for patients who have an expected survival of more than 3 months. It is contraindicated in patients who have preexisting myelosuppression, oncological urgencies or emergencies, renal insufficiency, pregnancy, or disseminated intravascular coagulation.

Muscle Relaxants

Pain originating from connective tissue injury is common in patients with cancer; however, use of muscle relaxants as adjuvant agents has had limited evaluation in patients with cancer. In a small study of 25 patients with neuropathic cancer pain, baclofen was effective in reducing pain score. Use of muscle relaxants has been associated with psychosis as well as insomnia, decreased appetite, poor concentration, irritability, disorganized thoughts, persecutory delusions, and auditory hallucinations. Muscle relaxants like cyclobenzaprine are structurally related to tricyclic antidepressants and share not only structural similarity but similar adverse effects. Dose tapering after treatment for a prolonged time is necessary to prevent withdrawal. In a review comparing the efficacy and safety of muscle relaxants, Chou and colleagues found limited or inconsistent data to supporting meaningful differences.

Octreotide

Pain, along with nausea and vomiting, is a common symptom associated with malignant bowel obstruction. Nonsurgical management of malignant bowel obstruction focuses on the management of pain and other obstructive symptoms, such as distension, nausea, and vomiting. The use of parenteral opioids, antiemetics, and antisecretory agents, such as octreotide, are common methods of pharmacological symptom control. Octreotide has been shown to have analgesic properties in specific conditions such as abdominal pain or headaches. ^,

Adjuvant Combinations

The treatment of neuropathic pain frequently requires several adjuvants. For example, it is not unusual for a patient with severe, cancer-related neuropathic pain to require an opioid or several additional adjuvants. When this occurs, the clinician should monitor the patient for potential drug interactions.