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10 Articles in Volume 13, Issue #4
Traumatic Brain Injury
US Service Members With Polytrauma
Cancer Patient: Controlling The Pain
Pharmaceutical Treatment of the Cancer Pain Patient
Drug Interactions in Cancer Patients Requiring Concomitant Chemotherapy and Analgesics
How Do We Get Enough Physicians to Medically Manage The Difficult (High-dose Opioid) Pain Patient?
Ultra-high Dose Opioid Therapy: Uncommon and Declining, But Still Needed
Head Trauma: More Than A Headache
Ask the Expert May 2013
Letters to the Editor May 2013

Pharmaceutical Treatment of the Cancer Pain Patient

Approximately 33% of cancer patients experience long-term pain. Many cancer patients are living longer, shifting pain management from a focus on acute pain to chronic pain. Part 2 of this four-part series on cancer pain will discuss practical aspects of pharmacologic cancer pain management.

Pain is a common manifestation of neoplastic disease. Cancer treatments including cytotoxic chemotherapy, radiation, surgery, and various interventions may contribute in differing degrees to the development of pain syndromes that are often worsened by daily stressors, anxiety, and depression.1 The prevalence of cancer pain increases depending on length of patient survival from time of diagnosis through treatment.2 For example, newly diagnosed cancer patients tend to have a lower prevalence of pain compared with patients undergoing active cancer treatment (25% vs 33%, respectively),3,4 and patients with advanced disease report the highest prevalence of pain (75%).2

This series of articles will review current concepts in the compassionate and multidisciplinary treatment of cancer-related pain—with this article providing a practical guide to pharmaceutical management.

Barriers to Treatment of Cancer Pain

Many national and international cancer care organizations have endorsed the use of opioids for the appropriate treatment of cancer-related nociceptive and neuropathic pain of peripheral origin.5 The success of treatment relies on adequate communication of the intensity and character (including persistent and breakthrough characteristics) of the patient’s pain, as well as realistic treatment expectations and goals, with treatment agreements and informed consent. These communications can be hampered when a patient under-reports their pain because they are in denial about progression of their cancer or when there is lack of correlation between the patient’s and the health care provider’s perceptions of the patient’s pain.6 Determination of the pain generator (Editor’s Note: Part 1 of series) can be associated with a different therapeutic approach or sense of urgency tailored to a patient’s individual pain problem.7

However, there continues to be a global lack of training in pain management for providers, resulting in the educational focus on diseases rather than symptoms. Pain management issues are infrequently highlighted at hospital rounds or educational conferences, resulting in providers’ lack of opioid-prescribing skills including equianalgesic opioid doses. There also continues to be major concerns regarding the regulatory oversight of opioid prescribing, including a recent FDA hearing to reclassify hydrocodone as a DEA schedule II (as recently enacted in New York), which would allow labeling that limits the duration, allow dosing recommendations for opioids used for non-malignant pain, and propose criterion for labeling abuse-deterrent formulations.

The good news is that there is widespread acceptance by pain specialists that opioids are efficacious and should be the mainstay of treatment, particularly for malignant pain.6 Regulatory and law enforcement organizations have recognized that appropriate opioid prescribing is part of the "standard of care" in appropriate patients, and under treating this pain also can be subject to disciplinary action. There are more convenient formulations, including tamper-resistant products. There are FDA-mandated risk evaluation and mitigation strategies (REMS) aimed at providers, patients, and pharmacists to ensure proper education about these medications.8 Many of the concepts presented in this article also may be applied to non-malignant pain.

Why Use Opioids?

Opioid analgesics are an efficacious treatment option for cancer pain. For persistent pain, which requires an around-the-clock (ATC) medication regimen, it is preferable to use long-acting formulations to improve patient compliance with potentially less euphoric side effects and reduced concerns of behavior aberrancies. However, these formulations tend to be more expensive and have a greater risk of causing sleep-disordered breathing (central sleep apnea).9 The dosing frequency may be increased, if necessary, for titration of analgesic control. To treat breakthrough cancer pain (BTP), additional analgesics are prescribed—including short-acting, oral, or rectal opioids—with supplemental rapid-onset opioids, currently classified as transmucosal immediate-release fentanyl (TIRF) products (Table 1). (Editor’s Note: Breakthrough Cancer Pain Treatments).10 In institutions providing palliative care, parenteral opioids—including morphine, hydromorphone, and fentanyl—have been used in conjunction with patient-controlled analgesia.11

As noted, many pain organizations have attempted to facilitate compassionate and effective pharmacologic cancer pain management. Opioids should be considered first-line therapy for patients with moderate to severe pain related to cancer, acquired immune deficiency syndrome, or other life-threatening illness. They should also be considered for any appropriate patients with moderate to severe non-cancer pain.5 This concept has been endorsed by many national and international pain societies including the World Health Organization (WHO). (Learn more about WHO).

Opioid Formulations

The majority of patients with advanced cancer stages (III and IV) have pain, with 54% having pain that is at least of moderate intensity. The "red flag" for investigation of active cancer-related pain is spontaneous onset, particularly with intensification during sleep or lying down. A decision to initiate opioid therapy is based on the severity of the pain, anticipated efficacy, minimization of side effects, stratification of risk of potential aberrancy, and the reasonable alternatives, both pharmacologic and nonpharmacologic. For refractory cancer pain patients, the subcutaneous route (avoiding intramuscular administration) can be effective for the administration of morphine and hydromorphone, and it should be considered a viable choice for appropriate patients unable to receive opioids by oral or transdermal routes, particularly if they are in institutions. Intravenous (IV) infusion should be considered when subcutaneous administration is contraindicated (peripheral edema, coagulation disorders, poor peripheral circulation, and need for high volumes and doses). IV administration should be used for opioid titration when rapid pain control is needed.12 In general, the equivalent IV dose is 1/3 the oral dose, subdural injections are 10 times more potent than IV administration, and intrathecal (subarachnoid) injections are 10 times more potent than subdural administration. Transdermal, rectal suppositories (which may require a compounding pharmacy formulation) or transmucosal delivery systems are preferred in those with alimentary problems (ie, cachexia, dysphagia, nausea, or vomiting).13 A recent meta-analysis has concluded that there are no important differences between morphine, oxycodone, and hydromorphone given by the oral route and that any one of these 3 drugs can be used as the WHO’s first choice in step III.14

Immediate-release and slow-release oral formulations of morphine, oxycodone, oxymorphone, and hydromorphone can be used for dose titration,14 though I have personally observed a higher side effect profile with morphine. Opioids prescribed on a regimen basis (which may be long-acting formulations) given ATC may be supplemented with oral immediate-release opioids as needed, with consideration of transdermal long-acting preparations (fentanyl or buprenorphine) for minimizing constipation side effects, and the patient’s preference.

Methadone may be considered a later choice for moderate to severe cancer pain, but should only be prescribed by experienced professionals. It has a complex pharmacokinetic profile and dual mechanism of action,13 including the N-methyl-D-aspartate (NMDA) receptor antagonist, which may prevent a tolerance effect, and an unpredictably long half-life. There also are cardiotoxic effects (QTc prolongation) and, rarely, rhabdomyo-
lysis, with abuse. It also may result in dental decay due to its anticholinergic effects on saliva.

How to Titrate Doses

Opioid dose titration over time is critical for successful opioid therapy with a goal of meaningful pain reduction with continued function and minimized side effects. The dose is gradually increased until there is adequate analgesia and function is improved, or until there are intolerable and unmanageable side effects. There is no "maximal" or "correct" dose. The responsiveness of an individual patient to a specific drug cannot be determined unless the dose increased to treatment-limiting toxicity.15 Based on the opioid formulations, the dose titration can be adjusted either every 4 to 24 hours in a hospital setting for short-acting medications or every 2 to 7 days (longer for fentanyl, buprenorphine patch, or methadone) on an outpatient basis. For long-acting formulations, conservative adjustments (increases of 20%-50%) can be made to prevent complications and side effects. It takes approximately 3 days on a new dose regimen to reach a new steady state.12

Traditionally, 10% to 15% of the daily ATC opioid dose has been used to treat an episode of BTP.15 However, there are no controlled trials indicating that this is an effective way to manage BTP. Studies have shown no simple linear relationship between the dose of an ATC medication and the dose required to treat BTP.16 Alternatively, increasing the ATC pain medication to treat BTP can result in overmedication and increased adverse effects, such as sedation, constipation, and confusion.17 In a recent cancer pain treatment guideline, there is a strong recommendation that BTP should be treated with additional doses of immediate-release oral opioids (and if necessary, TIRF products), and that an appropriate increased dosing of ATC should be considered. Additionally, there is a weak recommendation that immediate-release formulations of opioids with short half-lives should be used preemptively to treat predictable episodes of BTP in the 20 to 30 minutes preceding precipitating activity (such as moving the patient or procedure).13

Intraspinal opioids are an important advancement in pain therapy. Excellent pain relief has been reported in 73% of cases of intractable cancer pain.12 This route of delivery is generally preferred for long-term use in selected patients who have a life expectancy of at least 3 to 6 months, have intolerable side effects when opioids are administered through other routes, and are incapacitated by pain, with a threshold of at least 200 mg of oral morphine equivalent per day. It is important to properly select the appropriate patients since they need good patient compliance and realistic expectations with psychological clearance. Intrathecal analgesia (spinal pump) most frequently is used, but it may result in epidural granulomas and technical problems at higher opioid concentrations. Precautions should also be used for patients who are at risk for infections, especially with Staphylococcus aureus, and those who require regular diagnostic magnetic resonance imaging scans, which can affect pump function. Pharmacotherapy may include opioids (morphine, hydromorphone, and fentanyl) as well as clonidine, bupivacaine, baclofen, or ziconotide. Catheters may be tunneled subcutaneously and exit the skin or be connected to a subcutaneous port. A continuous ambulatory drug delivery pump may be placed on a waist belt.12

Opioid Adherence

As noted earlier, pain practitioners should not fear disciplinary action from medical, pharmacy, or nursing boards for ordering, prescribing, dispensing, or administering controlled substances, including opioid analgesics, for a legitimate medical purpose (based on the diagnosis and documentation of unrelieved pain). Many state medical boards require a complete evaluation (history and physical), treatment recommendations (including goals), informed consent with treatment agreement, periodic re-evaluations with adherence monitoring, consultative care (recommended at least annually), and meticulous medical record keeping/documentation in accordance with all applicable state or federal laws for controlled substances.18 The frequency of office visits should be at least every 3 months, and preferably monthly in stable patients on opioid therapy. To identify appropriate candidates for opioid therapy, the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine developed definitions of opioid use paradigms (Table 2).19

There are a number of opioid risk scales available to help clinicians screen potential patients for possible aberrant behaviors.20-30 Some of these are listed in Table 3. These screening tools are performed in conjunction with adherence testing of prescribed medications (ie, urine, saliva, or serum drug testing with expected metabolites), prescription drug monitoring programs, along with appropriate consultative care (ie, psychiatrist or addictionist) especially with higher-dose opioids (above morphine 90-120 mg/d or equivalent).31,32 Proper education for the patient and for his/her support system is necessary to convey the efficacy and risks, with informed consent, and is vital to properly monitor for treatment benefits and behavioral aberrancies.33 This can improve patient compliance and allow the providers to properly titrate the analgesic regimen. However, universal precautions for pharmacologic pain management are recommended in all patients, including those at seemingly low risk.34 The incidence and prevalence of opioid addiction (for all etiologies) has been reported to be as high as 24% (median 0.5%) and 31% (median 4.5%), respectively; the number is in the lower range for cancer patients.35

Chronic Opioid Therapy

Ultra-high dose opioid therapy (>1,000 mg/d of oral morphine equivalents) may be required in selected cancer patients for palliative care to achieve maximal comfort and function in the patient without causing sedation or physical impairments. These patients should be free of significant psychological or substance abuse disorders, and other medications (especially sedatives), should be minimized. Careful monitoring and documentation is needed. One can monitor these patients for serum opioid levels, particularly methadone (to avoid toxicity). Very low levels relative to the dosage may indicate malabsorption or a genetic liver enzyme defect (at least 33% may have a cytochrome P450 genetic variant), while very high opioid serum levels may indicate a liver enzyme defect or some resistance in the blood brain barrier or opioid receptor sites.36 (Editor’s Note: For more on ultra-high dose opioids).

Potential Side Effects

Pain clinicians should be aware of several well-documented side effects of opioid therapy. The most common opioid-related side effects are: constipation, somnolence, mental clouding or euphoria (caution with driving and machinery), nausea, and vomiting. It is prudent to initiate a prophylactic bowel regimen at the same time opioids are prescribed because tolerance to the constipating side effect generally does not occur. Patients usually require a prophylactic combination of detergent and stimulant cathartics to treat opioid-induced constipation (OIC). This may include irritants and stool softeners (Colace) along with stimulant laxatives (Senokot), lactulose, bulk-producing laxatives (Metamucil), ascorbic acid, lubiprostone (Amitiza), linaclotide (Linzess), and subcutaneous methylnaltrexone (Relistor). The latter agent is reserved for severe OIC. Other non-parenteral formulations also are in development.6 Lifestyle changes, including a high-fluid, high-fiber diet with physical activity, also are important. Cold modalities to the abdomen and eating (gastric-colic reflex) can stimulate peristalsis. Heat may reduce abdominal cramping.

The treatment for nausea and vomiting may include oral, oral dissolving, rectal suppository, or parenteral phenothiazines (caution regarding additional respiratory depression), and anticholinergic agents. These agents include promethazine (caution regarding IV formulations), prochlorperazine, olanzapine, metoclopramide (caution regarding dystonic reactions), trimethobenzamide (not usually available), ondansetron (caution regarding serotonin syndrome due to 5-HT3 antagonist), cannabinoids, methscopolamine, and ginger.6

Psychostimulants (dextroamphetamine or methylphenidate) can be used to improve opioid-induced sedation and may even enhance the analgesic effects. Modafinil or armodafinil also may be considered. Other options include rotating the opioids, switching to longer-acting or rectal formulations, and discontinuing other central nervous system (CNS) depressants. Most patients on chronic, stable, opioid analgesic therapy alone appear safe to drive or operate machinery.6

In those with severe impairments of renal function (glomerular filtration rate <30 mL/min), opioids should be used with caution. There is a known metabolite of morphine that can accumulate and cause renal toxicity in stage III or IV chronic kidney disease. One should seek specialist advice before prescribing strong opioids for patients with moderate to severe renal or hepatic impairment.13

For patients on a transdermal patch, there may be a skin irritation or rash. One strategy is to apply a nasal steroid spray ("off label") to the skin, let it dry, and then apply the patch, with rotation of skin sites. One should avoid placing the patch directly over the painful region, because local heat can significantly increase absorption. If there is hyperhidrosis, apply the patch to a region with less sweat. If the patch falls off, one may use a bio-occlusive dressing over the patch. The date and time should be written on the patch to prevent inadvertent dose problems.6 The branded fentanyl patch (Duragesic) may be less susceptible to abuse than its generic equivalents.

Less common side effects of opioids include dizziness, hyperhidrosis, myoclonus, anxiety, pruritus, urinary retention, orthostasis, headache, antitussive effects (especially with codeine), and edema. For pruritus due to the release of histamines, one can treat with antihistamines (hydroxyzine is more effective than diphenhydramine), and consider another opioid, avoiding morphine. For the treatment of neurotoxicity including myoclonus, delirium, psychosis, or seizures (may be due to δ opioid receptor effect), one should lower the opioid dose or switch to another opioid (preferably rotate to a structurally dissimilar opioid, with consideration of methadone), give hydration to facilitate the excretion of the previous opioid, and employ the short-term use of anxiolytics (ie, benzodiazepines, if there is neuromuscular excitation or agitation). The resolution of opioid-induced neurotoxicity may take hours to days.6

A well-known side effect of chronic opioid therapy is the inhibition of secretion of the adrenocorticotropic hormone and gonadotrophic-releasing hormone, reducing cortisol, luteinizing hormone, follicle stimulating hormone, and testosterone levels. Chronic opioid therapy also can stimulate prolactin, growth hormone secretion, and pancreatic secretion of insulin and glucagon; increase antidiuretic hormone secretion; and have a variable response for thyroid-stimulating hormones. This may result in amenorrhea or galactorrhea in women. In men, hypogonadism results in a reduction of free testosterone (observed in up to 90% of males with cancer in remission and patients with chronic pain). One should reduce the opioid dose, switch to short-acting opioids, or initiate testosterone replacement if there are no contraindications (ie, prostate cancer). Buprenorphine has less of an effect on hypogonadism.37

All opioids are to be used cautiously in patients with respiratory impairments, particularly chronic obstructive pulmonary disease and sleep apnea (especially central), those taking monoamine oxidase inhibitors, and those with head injuries or seizures (especially if taking tramadol and meperidine, due to a toxic metabolite). Respiratory depression is most likely seen in opioid-naïve patients or with too rapid titration. One should avoid sedating and depressant medications (benzodiazepines, phenothiazines, barbiturates, alcohol, and carisoprodol) and should carefully monitor a patient’s respiratory status. Other precautions include dehydration, biliary colic, and intestinal obstruction.38

Opioid Rotation

Opioid switching or rotation often is done when pain is not well controlled and side effects limit dose escalation. This concept is based on significant intra-individual variation in response to different opioids with incomplete cross-tolerance (patient is more sensitive to the new opioid). However, a recent meta-analysis has found no well-controlled trials that support the practice of opioid switching. The apparent success rate of switching ranges from 40% to 80% and the most frequent switch is from morphine to hydromorphone, or fentanyl to methadone.39 The conversion ratios used were specific for patients in whom analgesia from the first opioid was satisfactory. Therefore, when the opioid is switched because of unsatisfactory analgesia, excessive side effects, or both, clinical experience suggests that the starting dose should be lower than that calculated from published equianalgesic ratios. In all cases, the dose needs to be titrated in accordance with clinical response.39,40

There is controversy surrounding whether the FDA guidance for equianalgesic dosing is accurate, and there may be a wide variance in published equianalgesic doses for all opioids, particularly methadone. This may be due to patient factors including pharmacogenetics (opioid receptor polymorphism), pharmacodynamics (mechanism of action, receptor binding, dose-response curve), and pharmacokinetics (dose formulation, bioavailability, distribution, half-life, metabolic pathways, and excretion).

Other strategies to prevent escalation of opioid usage without a meaningful change in response include a treatment agreement with the patient in which it is stipulated that within a reasonable period of time for dose titration and assessment, the continuation of opioid medications are contingent upon improved function and attention to better side-effect management (ie, avoid giving additional opioids for abdominal pain, which may be related to the constipation effects of the opioids). Non-pharmacologic strategies include physical, occupational, talk, and psychological therapy; alternative and complementary approaches; and a regimen of home exercises. There also are pharmacologic strategies to lower opioid requirements by adding a non-opioid or adjuvant analgesic. Generally, the pain clinician will prescribe an equianalgesic dose that is 50% to 75% of the potency of the original opioid with the following provisos:

  • Reduce less if pain is severe
  • Reduce more if medically frail, or elderly with renal or hepatic disease
  • Reduce less if using the same drug by a different route, or with similar opioid metabolites already present
  • Reduce transdermal fentanyl less, and be aware of the lag (24-36 hours) in the response due to the subcutaneous reservoir
  • Reduce methadone even more: 75% to 90%39 (recommended starting dose is <30 mg/day)41

Opioid rotation, as a concept, has been critically reviewed by Dr. Lynn Webster, who cautions about controversial conversions of the published tables on equianalgesic dosing (and how they may lead to catastrophic toxicity by a naïve practitioner), and the lack of scientific literature validating this concept and a "recipe" for successful titration (Table 4).42,43 Therefore, I suggest a "test dose" of the newly planned opioid added to the current regimen. If tolerated, approved by insurance, and accepted by the patient, then a period of transition is initiated whereby approximately half of the previously used opioid is converted into an "opioid rotation" (unless the patient was previously tolerant to the proposed regimen without complications and the patient has a track record showing good efficacy) over a 1- to 2-week period, and then fully converted within 4 weeks. Unfortunately, there are no studies to validate any specific conversion in the "real world." Most of the studies that led to FDA approval of branded long-acting opioids used a specific conversion and titration protocol for "successful" conversion for a study duration of usually 13 weeks, and, therefore, the package inserts only can endorse this method of conversion.

Unlike conversion between other opioids, conversions involving methadone are not linear and depend on dose. This makes methadone coversion very tricky. Therefore, primary care physicians who are not familiar with using methodone should get consultations regarding conversion.41,44 As noted, monitoring for QTc prolongation is recommended (electrocardiogram after 4 weeks, and annually thereafter, especially with methadone >80 mg/d) and methadone is relatively contraindicated in those patients with QTc >0.45.

Due to metabolic pathways, it may be predictable that a patient who is previously intolerant to codeine, hydrocodone, and oxycodone may have side effects to morphine, hydromorphone, and oxymorphone, respectively, due to similar active metabolites. This is because methadone, buprenorphine, tramadol, codeine, hydrocodone, oxycodone, and fentanyl are metabolized by hepatic cytochrome P450 (especially CYP2D6 with codeine, hydrocodone, oxycodone, and tramadol; and CYP3A4 with buprenorphine, methadone, and fentanyl) and may result in unpredictable drug interactions with certain antibiotics, antifungals, antivirals, antidepressants, nicotine, alcohol, and cardiac medications. The P450 metabolic products of oxycodone, codeine, and hydrocodone, as well as oxymorphone, hydromorphone, morphine, and tapentadol, are metabolized primarily by liver glucuronidation, which is generally affected only with severe hepatic impairment, and, predictably, has fewer drug–drug interactions. However, all opioids have a class effect of drug interactions with sedatives and should be used with caution in those with impaired respiration. Tramadol and tapentadol have a maximal dose ceiling and have drug interaction precautions due to serotonin or neuroleptic malignant syndrome with many psychotropics, including antidepressants and antiemetics.13

A decision to initiate opioid rotation in patients who had previously been exposed to a similar metabolite is less likely to have an equivalent dose reduction when the dose conversion is completed, and may be more likely to have a quicker tolerance effect to the new formulation. In some patients, remaining on the same opioid formulation (for long- and short-acting effects) may minimize polypharmacy and side effects, and allow easier adherence assessment.Newer studies have suggested that combining 2 different opioid molecules simultaneously may saturate the µ opioid receptors at lower total daily dosing, and can optimize an analgesic effect (ie, a combination morphine and oxycodone fixed-dose drug is being developed), with fewer adverse effects. The decision about which opioid(s) to use for opioid rotation is based on the provider’s clinical experience, comfort level in prescribing various opioids, individual patient responses and variability, compliance concerns, and access to medications (costs including preauthorization and copays, pharmacy availability, and quantity limits per month, or limits on the number a prescriptions written per month for controlled substances). Other considerations are to use short-acting oral formulations on a time-contingent basis or transdermal/transmucosal formulations in patients with limited oral intake, gastroparesis, gastric bypass, blind loops, or short bowel syndrome. For dialysis patients, provisions for extra dosing should be available during hemodialysis days, since most non-lipophilic opioids are dialyzable.

Summary

The use of opioids for chronic pain (cancer and non-cancer) continues to require a careful balance of efficacy—including assessment of benefit–risk and safety concerns for the patient and society. Specific decisions involving choice of medication, doses, interval between doses, and titration regimens are based on individualizing treatment, clinical experience, and expert opinion ("the art of medicine"), with limited evidence-based data. In addition, there has been increased regulatory scrutiny affecting these decisions.

The above discussion of analgesics for cancer pain management may parallel chronic opioid therapy for non-malignant pain in appropriate patients, though additional supportive documentation, thorough monitoring, and stricter precautions are recommended. Opioid therapy should be viewed in the context of the "art" of multidisciplinary pain management including rational polypharmacy, with inclusion of non-opioid analgesics and adjuvants as well as nonpharmacologic options (Part 3).

Last updated on: June 25, 2015
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Non-Opioid Pharmaceutical Treatment of Cancer Pain
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