Limitations of Pharmacologic Pain Management
Pain Management, Chapter 128, 941-945
Chapter outline
- Risk-to-Benefit Ratio 941
- Pharmacologic Dichotomy: Cancer Pain and Chronic Nonmalignant Pain 941
- Role of Invasive Procedures 942
- Advantages of Pharmacotherapy for Cancer Pain 942
- Limitations of Pharmacotherapy for Cancer Pain 942
- Limitations of Pharmacotherapy for Noncancer Pain 943
- Specific Situations 943
- Neuropathic Pain 943
- Movement-Related Pain (Breakthrough or Incident Pain) 943
- Narrow Therapeutic Window: Cachexia and Advanced Age 944
- Suffering 945
- Abdominopelvic Pain 945
- Conclusion 945
Risk-to-Benefit Ratio
All medical interventions are associated with risks and benefits that, when considered together, constitute that intervention's risk-to-benefit ratio . Alternatives exist for all interventions (including no intervention), and these alternatives also possess their own risk-to-benefit ratios. Clinical decision making involves comparing and contrasting the risk-to-benefit ratios of alternative interventions (relative risk-to-benefit ratio) .
The risk-to-benefit ratio is multiply determined and is usually inexact. It is, in part, intrinsic to a given therapy, and it also, in part, depends on the clinical situation for which treatment is under consideration. How the risk-to-benefit ratio is determined or interpreted is influenced by numerous factors, some of which are difficult to quantitate (e.g., provider bias, patient preference) or have an ambiguous value (e.g., cost, patient suffering). As a result, the perceived risk-to-benefit ratio may differ profoundly based on interrelated factors pertinent to the patient (e.g., age, overall health, functional status, ethnocultural and religious background), the physician (e.g., attitudes, beliefs, training, financial incentives), and the system (e.g., regulatory forces, facilities, economic factors). The risk-to-benefit ratio is not a fixed entity but instead varies as these factors and their relationships with each other change over time. This situation is further complicated when applied to the treatment of pain because as a result of the subjective nature of pain and the newness of pain management as a specialty, data regarding the outcomes of even accepted interventions are scarce. In the past, this allowed for wide latitude in decision making. However, increased scrutiny of health care costs is likely to be associated with greater constraints on decision making.
Pharmacologic Dichotomy: Cancer Pain and Chronic Nonmalignant Pain
Cultural and social forces have profound influences on therapeutic decision making regarding the treatment of pain with medications. A curious but contextually understandable dichotomy exists with respect to the treatment of pain of malignant versus nonmalignant origin with opioid analgesics.
Cancer Pain
Until relatively recently, opioids were avoided for all but the most desperate medical conditions. This stigmatization was based more on cultural bias than on medical fact. Initiatives emphasizing the concept of comprehensive cancer care mandate attention to symptom control throughout the course of a malignant illness. Contemporary approaches to managing pain in cancer patients emphasize earlier and more liberal use of opioids, and investigators cite a low potential for addiction and a generally favorable risk-to-benefit ratio. A review of the literature suggests that these principles are grounded firmly in science.
Chronic Pain
Opioids were long considered taboo as treatment for chronic nonmalignant pain. These concerns were mostly grounded in beliefs about the inevitability of addiction and typically reflected not just medical concerns but moral views as well. In light of data generated by opioid use in cancer pain, the prohibition of opioid therapy for noncancer pain has been called into question. A spectrum of opinion currently exists regarding the advisability and proper methodology for prescribing opioids in such patients. Although both proponents and detractors cite data that support opposing views, investigators agree that opioid therapy is more beneficial than harmful in a proportion of patients with chronic nonmalignant pain. Although reasonable scientific support exists for this general contention, support for guidelines to determine the risk-to-benefit ratio prospectively in individual cases remains empirical.
Role of Invasive Procedures
In the treatment of both cancer and noncancer pain, evidence-based support of the role of interventional pain-relieving modalities is less well defined than is support for the use of drugs. The situation is analogous to that of opioids for nonmalignant pain. Although fairly widespread agreement exists that procedures sometimes possess favorable risk-to-benefit ratios, a uniformly accepted, validated methodology is lacking for prospectively determining which settings are valuable for certain procedures.
Cancer Pain
Although the use of interventional pain management modalities in the treatment of cancer pain has been well accepted in the clinical arena for decades, the more recent aggressive use of systemic opioids and adjuvant analgesics combined with the increased use of the spinal administration of opioids has reduced the frequency of neurodestructive procedures in the management of cancer pain. Certain procedures, such as celiac plexus neurolysis, radiofrequency lesioning of intercostals nerves, transsphenoidal pituitary neurolysis, and gasserian ganglion neurolysis continue to have a significant place in cancer pain management.
Chronic Pain
Debate over the role of interventional procedures for chronic nonmalignant pain is, if possible, even more contentious that the debate over the use of these modalities for cancer pain management. Evidence has been cited supporting diametrically opposed views, and the quality of such evidence has legitimately been questioned. Factors influencing this debate are as noted previously but also include bias (even rivalry) among specialists, third-party and governmental payers, financial stake, and opiophobia. Limited reasonable agreement remains among these parties regarding when, and in whom, certain procedures provide sufficiently meaningful and durable pain relief to justify their risks and costs. Agreement exists that the outcomes for procedures are most favorable when they are “properly” integrated within a multidisciplinary matrix, although the evidence for even this conventional wisdom is questionable. Because of the subjective nature of pain and the difficulty in blinding subjects to the administration or withholding of local anesthetics in nerve blocks, evidence-based outcomes will continue to remain elusive, although downward pressure on health care spending may make the matter moot.
Advantages of Pharmacotherapy for Cancer Pain
For various reasons, oral opioid therapy is considered the treatment of choice for uncomplicated cancer pain. These reasons include the induction of analgesia that is reversible, titratable, and suitable for different types of pain, including multiple topographically distinct pains, generalized pain, and lack of invasiveness. Furthermore, the risk-to-benefit ratio of properly administered opioid therapy in this clinical setting further promotes its use. The need for specialized training is modest, and efficacy is maintained when treatment is modified to apply to individuals across cultures and over a range of ages and medical fitness.
Limitations of Pharmacotherapy for Cancer Pain
In 70% or more of cancer patients, pain relief is known to be achieved with uncomplicated oral or transdermal administration of opioids, especially when combined with nonsteroidal antiinflammatory drugs (NSAIDs) and adjuvant analgesics (e.g., antidepressants, anticonvulsants). Up to 30% of all patients with cancer pain, however, require alternative interventions to achieve comfort. The construct that opioids should be administered in doses sufficient either to control cancer pain or to produce unacceptable side effects is widely accepted because this class of drugs has no ceiling effect, unlike the NSAIDs and most adjuvant analgeics. Although the end points of opioid therapy (i.e., comfort and unacceptable side effects) are difficult to quantify, this view recognizes unacceptable side effects as one possible consequence of drug therapy. These side effects constitute the most important limitations of drug therapy for cancer pain.
Several investigators have attempted to identify specific clinical findings that, when identified prospectively, signal that pain relief will be difficult to achieve by pharmacologic means alone. The best validated schema, the Edmonton Staging System, suggests that the presence of a history of alcohol or drug abuse or recent tolerance, neuropathic pain, psychological distress, and movement-related pain predict a relatively poorer prognosis for controlling pain pharmacologically, whereas drug dose and the presence of delirium are not predictive. Other investigations suggest that incident and movement-related pain (kinesophobia) is the only consistent predictor of poor outcome for pharmacotherapy. This constitutes an extremely important area for further study, especially with methodologies that target specific clinical pain syndromes. Experience suggests that syndromes such as tumor-mediated brachial and lumbosacral plexopathy, abdominopelvic pain, and pain from the skin ulceration that accompanies fungating tumors are among other daunting syndromes in which pain often persists despite aggressive drug therapy. Although no single feature reliably predicts failure of pharmacotherapy, the presence of these features should alert the clinician that additional resources may be needed to help manage pain effectively.
Limitations of Pharmacotherapy for Noncancer Pain
The historical view that the use of opioids was prima facie undesirable for the management of chronic pain allowed for a ready determination of risk-to-benefit ratio, no matter how unscientific. Contemporary views that opioid therapy for noncancer pain is justified in selected patients call for a general reappraisal of risk-to-benefit ratio and carefully individualized decision making.
The baseline limitations of drug therapy for nonmalignant pain include the same potential side effects that restrict drug use in cancer patients. Additional limitations in this population depend on the degree to which a given patient is perceived as being at risk for addiction and the degree to which the practitioner perceives opioid therapy as being potentially effective and appropriate.
Specific Limitations
Dose-Limiting Side Effects
One set of limitations relates to the various collateral (nonanalgesic) effects of the analgesics. The most prominent side effects of the opioids are constipation, nausea, vomiting, cognitive failure (ranging from drowsiness to hallucinations), dysphoria, myoclonus, and pruritus, although other side effects such as respiratory depression occasionally supervene. Similarly, treatment with the NSAIDs and other adjuvants is limited by undesirable pharmacologic side effects such as gastropathy, bleeding, renal insufficiency, masking of fever, sedation, constipation, dry mouth, dysrhythmias, cognitive failure, ataxia, hepatic insufficiency, and bone marrow depression.
Drug side effects, especially opioid, can often be managed effectively. Strategies for managing opioid side effects in cancer patients are depicted in Table 128.1 . Side effects of simple analgesics, NSAIDs, and adjuvant analgesics may be more problematic and are in many cases less readily reversible. Thus, an important distinction between the opioids and other analgesics is that opioids have few absolute contraindications, whereas the other analgesics often need to be avoided altogether lest complications occur (e.g., aspirin in the patient with an ulcer, hypersensitivity, or bone marrow depression). Paradoxically, for long-term use, the opioids are both the most stigmatized of all analgesics and, on a physiologic basis, arguably the safest.
Table 128.1
Strategies for Limiting the Side Effects of Opioids
| Strategy | Comments |
|---|---|
| Prophylaxis | This approach is used especially for constipation and sometimes for nausea |
| Patient education | Informed of the potential for side effects, patients are less likely to assume they are allergic and more likely to cooperate with efforts at palliation |
| Patience | Nausea and sedation are usually transitory and remit with time |
| Slower titration may reduce troublesome side effects | |
| Symptomatic management | Treat with antiemetics, laxatives, psychostimulants, etc. |
| Trials of alternative (related) analgesics | Efficacy: side effect profile of opioids is often idiosyncratic |
| Trials of alternative opioids are indicated because of incomplete cross-tolerance | |
| Trials of adjuvant analgesics | Side effects may result from reliance on opioids for a pain syndrome that is relatively nonresponsive to opioids |
| Successful therapy with adjuvants may allow for a reduction in opioid dose with fewer side effects | |
| Alternate treatment modalities | Judicious application of antitumor therapy, procedures, psychotherapy, etc., may permit dose reductions with fewer attendant side effects |
Specific Situations
Besides the general category of dose-limiting side effects, certain clinical situations impose specific limitations or increased risks from pharmacotherapy. Only a few such issues are cited here.
Neuropathic Pain
Somatic and visceral nociceptive pain typically responds linearly to escalating doses of opioid analgesics. In contrast, the dose-response relationship for neuropathic pain is often blunted. Treatment in higher dose ranges is required, as a result of which side effects are more likely to be problematic. Although neuropathic pain syndromes were once considered an opioid-nonresponsive set of disorders, the range of response observed for these syndromes forms the basis for the concept of relative responsivity to opioids. Increasingly, neuropathic pain syndromes are successfully treated by an approach that uses maintenance therapy with low-dose opioids for the induction of partial analgesia, after which sequential trials of adjuvant analgesics are conducted in an effort to gain more complete analgesia.
Movement-Related Pain (Breakthrough or Incident Pain)
The tempo of chronic pain is most often one of continuous, unrelenting, low-grade basal pain, punctuated by episodic exacerbations that can be unpredictable but that are most often related to activity. These superimposed flares are generally referred to as breakthrough pain . The basal component of pain is typically treated with a long-acting opioid administered on a time-contingent basis (by the clock), such as an oral controlled-release formulation of morphine or oxycodone administered every 12 hours, a transdermal preparation of fentanyl applied every 72 hours, or—less commonly—methadone. Breakthrough pain is then treated with the symptom-contingent administration of a second, short-acting oral opioid administered as needed (immediate- release morphine sulfate, hydromorphone, oxycodone, or oral transmucosal fentanyl citrate [OMFC]). The dose of long-acting medication is then titrated based on the frequency and urgency of the requirement for as-required treatment of breakthrough pain.
Breakthrough pain that has a relatively consistent temporal relationship with specific activities has come to be referred to as incident pain . Breakthrough pain that occurs at predictable intervals just before the next scheduled dose of an analgesic drug is referred to as end-of-dose failure . Breakthrough pain that appears to be idiosyncratic and unrelated to either activity or scheduled doses of analgesics is typically referred to as eitherspontaneous breakthrough pain or idiopathic breakthrough pain , or simply as breakthrough pain .
Pain that is exacerbated with movement is among the most difficult to control with analgesics. The pharmacokinetic properties of currently available drugs, even those administered intravenously, are not well matched to the often unpredictable, rapid, and wide fluctuations in severity of movement-related pain.
When incident pain is relatively unpredictable, rescue doses are provided prophylactically, approximately 30 minutes in advance of the pain-provoking activity. When unanticipated breakthrough pain occurs, the rescue dose should be taken as soon after onset as possible, independent of the timing of the basal dose. If these strategies are unsuccessful, the clinician should consider a trial of an alternative short-acting opioid or a change in the route of administration. Breakthrough pain that is predictable, infrequent, of mild or moderate intensity, or slow to develop can often be managed effectively with oral analgesics such as immediate-release (IR) morphine, hydromorphone, or oxycodone. Breakthrough pain that is severe or that occurs unpredictably, frequently, or precipitously may not be adequately relieved with currently available oral agents. Although intravenous and subcutaneous opioids are pharmacokinetically well suited for labile or severe breakthrough pain, these advantages are offset by the invasiveness of the route of administration.
OTFC, a newer formulation of the established opioid analgesic fentanyl, has been approved specifically for the treatment of breakthrough pain that arises in patients already using around-the-clock opioids. A sweetened fentanyl-impregnated lozenge mounted on a stick, it is a noninvasive means of delivering a potent lipophilic opioid through the oral mucosa, thus facilitating rapid absorption into the circulation and analgesia of relatively fast onset and short duration. Extensive controlled research was conducted on the use of OTFC as a specific remedy for breakthrough pain. This research confirmed the safety of this agent and demonstrated its superior efficacy to routine oral agents in cancer patients receiving concomitant therapy with immediate-release and controlled-release oral opioids for basal pain. The onset of meaningful analgesia typically occurs within 5 minutes of beginning consumption of a unit, peaks approximately 30 minutes later, and usually lasts approximately 4 hours. The duration of analgesia is slightly prolonged because approximately one half of each fentanyl dose is inevitably swallowed and is subjected to hepatic first-pass effect. The availability of fentanyl in a lozenge form allows for easy self-administration and permits patients to titrate the dose to an effective level of analgesia without the need for injections. An intranasal formulation of fentanyl may be a reasonable alternative that may have a faster onset of action.
Even with this addition to the treatment armamentarium, prominent incident pain remains a treatment challenge because opioid requirements vary dramatically over short intervals. Doses of opioids required to treat pain during periods of rest are typically inadequate when activity increases, and, conversely, doses required to ease movement-related pain may produce sedation and other side effects when the provocative activity decreases.
Narrow Therapeutic Window: Cachexia and Advanced Age
Although many patients with cancer are not candidates for curative therapy, palliative and supportive care may extend life. Pharmacologically based pain control is often more difficult to achieve in patients with advanced cancer because concomitant asthenia and cachexia increase the likelihood of side effects from opioids titrated to therapeutic effect (narrow therapeutic window) . The sedative effects of opioids can often be countered by the judicious use of psychostimulants, such as methylphenidate, which are usually administered at starting doses of 10 mg on awakening and 10 mg at the noon meal and can be titrated to effect. Although dysrhythmias and anorexia are theoretical concerns, they are rarely problematic, although psychostimulants should be avoided in the presence of an anxiety disorder or brain metastases.
Limited epidemiologic data suggest that chronic pain is about twice as common for geriatric individuals living in residential settings than in their younger counterparts; the incidence in older persons ranges from 25% to 50%. Although underrecognition and undertreatment of pain in nursing homes are so rampant that statistics are often misleading, targeted surveys reveal an incidence ranging from 45% to 80%.
Degenerative arthritis and other musculoskeletal disorders are the most prominent sources of pain in older patients, although herpes zoster, decubitus ulcers, peripheral vascular disease, temporal arteritis, and polymyalgia rheumatica are disproportionately common with advanced age. Because the incidence of almost all malignant diseases increases with advancing age, oncologic pain is a particularly common problem in the geriatric population. It is an especially important problem because many of the factors that cause cancer pain to be undertreated in the general population are amplified in aging patients.
Although some degree of age-associated changes in organ function (including the central nervous system) are ubiquitous, with a few exceptions these changes ordinarily exert little influence on pain threshold or pain tolerance, although pharmacodynamics or pharmacokinetics may be somewhat altered. Loss of neuronal tissue and proliferation of glial cells occur with advancing age, but no evidence indicates impairment in processing pain signals unless dementia or delirium is clinically evident. Clinical lore suggesting that older patients do not experience pain as keenly as their younger counterparts is unfounded and is often no more than a rationalization for an unwillingness to spend the added time often required in assessing the older patient.
The hospice experience has demonstrated that, when appropriate time and effort are applied, pain can usually be managed effectively even in the frail, older patient. However, drug titration should be performed with considerable caution, and, when possible, polypharmacy should be avoided.
Suffering
Pain is determined in multiple ways and often persists as a result of unidentified psychosocial causes. Analgesics themselves are unlikely to reduce complaints of pain that are rooted in more global suffering. Psychotropic drugs combined with psychotherapy may, however, be effective in this setting.
Abdominopelvic Pain
Factors specific to patients with abdominopelvic pain that reduce the likelihood of attaining adequate pain control with systemic analgesics alone are listed in Table 128.2 . NSAIDs, even of the cyclooxygenase-2–selective type, may be poorly tolerated or contraindicated owing to gastropathy and to general factors such as renal insufficiency, coagulopathy, bone marrow suppression, and masking of fever. The oral route may be unreliable in the presence of gastrointestinal dysfunction (e.g., dysphagia, malabsorption, intestinal obstruction, nausea and vomiting, xerostomia, coma). Reduced gastrointestinal motility is a common upshot of tumor encroachment or a sequela of surgery or radiation therapy. Even with a strict bowel protocol, opioids may exacerbate ileus or partial obstruction in patients with reduced motility. In such cases, the use of opioids, except in low doses, is undesirable. Although visceral pain is relatively opioid responsive, patients often present with pain of mixed causes. Typically, pain resulting from nerve injury (neuropathic pain) is less sensitive to opioids, and thus occult microscopic deposits of perineural tumor invasion may contribute to reduced opioid responsivity. Early use of alternative routes of administration (e.g., transdermal, intranasal) may help to avoid many of the problems associated with abdominopelvic pain. Splanchnic, celiac plexus, and hypogastric plexus blocks are especially useful in this patient population.
Table 128.2
Potential Limitations of the Pharmacologic Management of Abdominopelvic Pain
| Treatment Modality | Limitations |
|---|---|
| Nonsteroidal anti-inflammatory drugs | GastropathyRenal dysfunctionBone marrow depletionConcerns about masking fever |
| Oral analgesics | XerostomiaDysphagiaMalabsorptionObstructionNauseaVomitingComa |
| Transdermal analgesics | Dose requirements for opioids possibly exceeding limitations of dose form |
| Parenteral analgesics | Inadequate household or community support to manage infusions |
| Opioids | IleusPartial obstructionIntractable constipationReduced responsivity resulting from neuropathic component of painDose-limiting side effects resulting from asthenia and cachexia |
Conclusion
Notwithstanding the controversy on opioids for chronic pain, data support the primary role of pharmacotherapy for managing most pain syndromes. Some patients do not derive adequate comfort from systemic drug therapy alone, however, or are not candidates for liberal use of opioids. Even for cancer pain, when addiction is less of a concern and liberal prescribing is widely endorsed, physiologic and psychological features sometimes hinder achieving an adequate pharmacologic remedy.
The most formidable limitations of drug treatment relate to their potential to produce pharmacologic side effects or complications. Careful monitoring and the use of strategies for preventing and managing drug side effects are often all that is required to maintain efficacy. Specific patient-related factors (e.g., neuropathic pain, movement-related pain, psychological distress, cachexia, alterations in gastrointestinal function) are associated with greater likelihood of limitations. The degree to which a selected drug's potential to induce habituation is an impediment to long-term use remains a topic of considerable and heated debate.
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