1. Pharmacotherapy of Pain: Opioid Analgesics

2. Evolving Role of Opioid Therapy
From the 1980s to the present
More pharmacologic interventions for acute and chronic pain
Changing perspectives on the use of opioid drugs for chronic pain
The role of opioid therapy in the treatment of chronic pain has been evolving. To apply this approach in practice appropriately, the clinician must continually decide how to position pharmacotherapy among a broad range of analgesic strategies, and, if pharmacotherapy is acceptable, how to position opioid therapy among the increasing number of analgesic drugs available.

3. Evolving Role of Opioid Therapy
Historically, opioids have been emphasized in medical illness and de-emphasized in nonmalignant pain
Historically, opioids have been stigmatized by their association with abuse, diversion, and addiction. The stigma means that the risks of these drugs often are exaggerated. The perceived risks include tolerance, side effects such as mental clouding, and addiction. One result of this tendency to overstate the risks associated with opioid therapy has been to position them for the management of very ill patients—presumably a group that would not be much affected by these problems.

4. Opioid Therapy in Pain Related to Medical Illness
Opioid therapy is the mainstay approach for
Acute pain
Cancer pain
AIDS pain
Pain in advanced illnesses
But undertreatment is a major problem
The broad international consensus is that opioid therapy serves as the mainstay approach for treatment of pain associated with acute pain and pain due to serious illnesses, such as cancer. Notwithstanding, we have abundant evidence that undertreatment is common, even in these populations.

5. Barriers to Opioid Therapy
Patient-related factors
Stoicism, fear of addiction
System factors
Fragmented care, lack of reimbursement
Clinician-related factors
Poor knowledge of pain management, opioid pharmacology, and chemical dependency
Fear of regulatory oversight
Undertreatment can be assessed in contexts, such as cancer pain, in which there is consensus regarding the standard of care. In these contexts, undertreatment has been determined to be a complex phenomenon related to problems at multiple levels—patient, clinician, and system.

6. Opioid Therapy in Chronic Nonmalignant Pain
Undertreatment is likely because of
Barriers (patient, clinician, and system)
Published experience of multidisciplinary pain programs
Opioids associated with poor function
Opioids associated with substance use disorders and other psychiatric disorders
Opioids associated with poor outcome
We have no consensus about the role of opioid therapy in nonmalignant pain—and, hence, no certain data about the degree of undertreatment that exists. However, the individual and systemic barriers to opioid use, as well as the bias against opioid therapy that developed from the experience of multidisciplinary pain management programs, make undertreatment likely. The data published from the aforementioned programs do reveal associations between opioid use and negative characteristics and outcomes, and they suggest the potential for adverse responses to this therapy. However, because of the selection biases inherent in these programs, which attracted the most difficult patients, this experience cannot be used to evaluate the larger role of opioid therapy.

7. Opioid Therapy in Chronic Nonmalignant Pain
Use of long-term opioid therapy for diverse pain syndromes is increasing
Slowly growing evidence base
Acceptance by pain specialists
Reassurance from the regulatory and law enforcement communities
The role of opioid therapy has been evolving. Consensus statements from the American Pain Society, the American Academy of Pain Medicine, and the American Society of Addiction Medicine now endorse this approach in select patients. This change in the thinking of pain specialists, combined with a slowly growing evidence base and recognition on the part of those in the regulatory and law enforcement communities of the need to support legitimate prescribing, is leading to increased use of long-term opioid therapy by primary care providers.

8. Opioid Therapy in Chronic Nonmalignant Pain
Supporting evidence
>1000 patients reported in case series and surveys
Small number of RCTs
Support for the potential benefits of long-term opioid therapy has been suggested by a large number of surveys in diverse conditions and by a smaller number of randomized controlled trials (RCTs). Most of the RCTs evaluated select populations for relatively brief periods of time. The data from these trials must be generalized cautiously to the clinical setting because of the selection factors and limited relevance of trials that continue for brief periods. Nonetheless, the favorable outcomes of these surveys and studies provide a rationale for expanded use of this therapy.

9. Positioning Opioid Therapy
Consider as first-line for patients with moderate-to-severe pain related to cancer, AIDS, or another life-threatening illness
Consider for all patients with moderate-to-severe noncancer pain, but weigh the influences
What is conventional practice?
Are opioids likely to work well?
Are there reasonable alternatives?
Are drug-related behaviors likely to be responsible, or problematic so as to require intensive monitoring?
In the absence of empirically-derived guidelines based on predictors of success or failure, clinicians have no choice but to rely on clinical judgment, a limited existing evidence base, and common sense when deciding whether to start an opioid trial or begin a long-acting opioid with the intention of continuing long-term therapy. Influences on this decision include an understanding of conventional practices, including those now used by pain specialists, and inferences about the likelihood of effectiveness and responsible drug use on a patient’s part.

10. Opioid Therapy: Needs and Obligations
Learn how to assess patients with pain and make reasoned decisions about a trial of opioid therapy
Learn prescribing principles
Learn principles of addiction medicine sufficient to monitor drug-related behavior and address aberrant behaviors
To make judgments about starting, continuing, or increasing opioid therapy, clinicians must have information about other options that could be used to treat the pain and disability of their patients. Clinicians must perform an assessment that allows consideration of a variety of modalities, including both pharmacologic and nonpharmacologic approaches. They must know enough about prescribing principles to administer the drug in a safe manner that optimizes the analgesic regimen. Finally, they must have a sufficient grasp of the principles of addiction medicine to allow astute monitoring of drug-related behaviors.

11. Opioid Therapy: Prescribing Principles
Drug selection
Dosing to optimize effects
Treating side effects
Managing the poorly responsive patient
Many published guidelines reflect consensus views about the best approaches for management of long-term opioid therapy. The principles in these guidelines must be understood to optimize the likelihood of successful outcomes.

12. Opioid Therapy: Drug Selection
Immediate-release preparations
Used mainly
For acute pain
For dose finding during initial treatment of chronic pain
For “rescue” dosing
Can be used for long-term management in select patients
Immediate-release opioids are usually used for a limited period to treat acute pain or to help identify a useful starting dose for a long-acting drug. These drugs can be administered on a long-term basis as well, usually as supplemental doses given “as needed” to patients who are receiving a concomitant long-acting drug (an approach known as “rescue” dosing).

13. Opioid Therapy: Drug Selection
Immediate-release preparations
Combination products
Acetaminophen, aspirin, or ibuprofen combined with codeine, hydrocodone, dihydrocodeine
Single-entity drugs, eg, morphine
Tramadol
Short-acting opioids include the combination products, single-entity pure mu-agonists, and tramadol. Dose escalation of the combination products is subject to the limits of safe dosing with the nonopioid constituent. Acetaminophen-containing combinations, for example, generally should not be given at doses that deliver more than 4 grams of acetaminophen per day. Single-entity drugs, such as morphine, oxycodone, and hydromorphone, have no such top doses. Tramadol is a unique centrally-acting analgesic that acts via both an opioid mechanism and a nonopioid, monoaminergic mechanism.

14. Opioid Therapy: Drug Selection
Extended-release preparations
Preferred because of improved treatment adherence and the likelihood of reduced risk in those with addictive disease
Morphine, oxycodone, fentanyl, hydromorphone, codeine, tramadol, buprenorphine
Adjust dose q 2–3 d
Numerous extended-release formulations are available in different countries. The oral drugs allow dosing 1 to 3 times per day and the transdermal drugs allow dosing every 2 to 3 days. Usually, steady-state is approached with these formulations within a few days and dose adjustments are best made in this time frame.

15. Opioid Therapy: Drug Selection
Role of methadone
Another useful long-acting drug
Unique pharmacology when commercially available as the racemic mixture
Potency greater than expected based on single-dose studies
When used for pain: multiple daily doses, steady-state in 1 to several weeks
Methadone is gaining favor as another long-acting drug for the treatment of chronic pain. In many countries, it is available as the racemic mixture of the d-isomer and the l-isomer. The d-isomer does not bind to the opioid receptor, but is a NMDA-receptor antagonist and, as such, can both produce analgesia through an independent mechanism and partially reverse opioid tolerance. For this reason, the drug is usually more potent than would be expected on the basis of the equianalgesic dose table. The potential to reverse tolerance may explain why the potency of the drug appears to be directly related to the dose and duration of treatment with another mu-agonist prior to a switch to methadone. The latter observation suggests that methadone may be most useful when administered as a “second-line” agent. Methadone has a very variable half-life (ranging from 12 h to >150 h). Although most patients approach steady-state after a few days of dosing, some require a longer period of time.

16. Opioid Selection: Poor Choices for Chronic Pain
Meperidine
Poor absorption and toxic metabolite
Propoxyphene
Poor efficacy and toxic metabolite
Mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, dezocine)
Compete with agonists  withdrawal
Analgesic ceiling effect
Extensive experience suggests that some of the single-entity opioid drugs are poor choices for chronic pain. Meperidine is metabolized to normeperidine, accumulation of which is associated with tremulousness, dysphoria, hyperreflexia, and seizures. Propoxyphene at high doses has a similar problem. The mixed agonist-antagonists have a ceiling effect for analgesia that limits their efficacy during long-term use.

17. Opioid Therapy: Routes of Administration
Oral and transdermal—preferred
Oral transmucosal—available for fentanyl and used for breakthrough pain
Rectal route—limited use
Parenteral—SQ and IV preferred and feasible for long-term therapy
Intraspinal—intrathecal generally preferred for long-term use
Opioids may be delivered by numerous routes of administration. For long-term therapy, the oral and transdermal routes are preferred. The availability of the oral transmucosal formulation for fentanyl provided a novel method to treat breakthrough pain, one that appears to have a faster onset of effect than routine oral administration. Patients who cannot tolerate oral or transdermal therapy are sometimes candidates for long-term subcutaneous infusion. Intrathecal infusion via an implanted pump may be appropriate for patients who cannot tolerate the side effects associated with systemic therapy.

18. Opioid Therapy: Guidelines
Consider use of a long-acting drug and a “rescue” drug—usually 5%–15% of the total daily dose
Baseline dose increases: 25%–100% or equal to “rescue” dose use
Increase “rescue” dose as baseline dose increases
Treat side effects
The most common approach to long-term therapy involves coadministration of a long-acting drug and a short-acting drug, which is offered “as needed” for breakthrough pain. The size of the rescue dose is usually in the range of 5% to 15% of the total daily dose; studies of the oral transmucosal fentanyl formulation have not confirmed this ratio, however, and dosing with this drug should be started low and then titrated. Individualization of the scheduled opioid dose through a process of dose titration is critical to a successful outcome. Dosing increments can either be in the range of 25% to 100%, depending on the severity of the pain and concern about opioid toxicity, or be guided by the amount of rescue drug taken during the prior day. As the dose of the scheduled opioid is increased, the dose of the rescue also should be increased to maintain the dose as a percentage of the total daily dose. Side effects must be treated.

19. Opioid Therapy: Side Effects
Common
Constipation
Somnolence, mental clouding
Less common
Nausea – Sweating
Myoclonus – Amenorrhea
Itch – Sexual dysfunction
Urinary retention – Headache
For most patients, the goal during long-term therapy is to identify a favorable balance between analgesia and opioid side effects. The common side effects are constipation and mental clouding. Other side effects occur less often.

20. Opioid Responsiveness
Opioid dose titration over time is critical to successful opioid therapy
Goal: Increase dose until pain relief is adequate or intolerable and unmanageable side effects occur
No maximal or “correct” dose
Responsiveness of an individual patient to a specific drug cannot be determined unless dose was increased to treatment-limiting toxicity
Opioid responsiveness can be defined as the likelihood that a favorable balance between analgesia and side effects will be attained as the opioid dose is slowly titrated. A patient cannot be said to be a “nonresponder” unless the dose has been increased to the point of treatment-limiting side effects. Responsiveness varies with characteristics of a particular patient and his or her particular pain. Studies have suggested that responsiveness is inversely related to neuropathic mechanism, breakthrough pain, previous opioid exposure, cognitive impairment, and psychologic distress. However, no evidence exists that any characteristic imparts opioid resistance.

21. Poor Opioid Responsiveness
If dose escalation  adverse effects
Better side-effect management
Pharmacologic strategy to lower opioid requirement
Spinal route of administration
Add nonopioid or adjuvant analgesic
“Opioid rotation”
Nonpharmacologic strategy to lower opioid requirement
Surveys in the cancer population suggest that 10% to 30% of patients will experience a poor response to an optimally titrated opioid regimen. Poorly-responsive patients can be considered for a variety of alternative opioid strategies. These include: 1) more sophisticated management of opioid side effects (eg, a psychostimulant for opioid-induced sedation or mental clouding), 2) use of a pharmacologic approach to reduce the systemic opioid requirement (either a trial of intraspinal therapy or coadministration of a nonopioid or adjuvant analgesic), 3) opioid rotation, or 4) a trial of a nonpharmacologic approach to reduce the opioid requirement (eg, a stimulatory, rehabilitative, anesthesiologic, surgical, or complementary approach). Comparative studies of these strategies have been conducted, and selection of one over another involves a detailed assessment, careful judgments about risks and benefits, and discussion of patient preferences.

22. Opioid Rotation
Based on large intraindividual variation in response to different opioids
Reduce equianalgesic dose by 25%–50% with provisos:
Reduce less if pain severe
Reduce more if medically frail
Reduce less if same drug by different route
Reduce fentanyl less
Reduce methadone more: 75%–90%
Opioid rotation is common practice and is based on the clinical observation of large individual variation in the response to different opioids. Guidelines for switching drugs assure safety and yield a reasonable starting dose of the new drug, which then must be titrated.

23. Equianalgesic Table PO/PR (mg) Analgesic SC/IV/IM (mg) 30 Morphine 10
4–8 Hydromorphone 1.5
20 Oxycodone -
20 Methadone 10
The equianalgesic dose table has been derived from well-controlled single-dose studies. It should be used as a guide only. In some cases, such as methadone, experience has shown that the dose ratios are very different from those that work in practice (at least when switching to methadone from another drug).

24. Opioid Therapy and Chemical Dependency
Physical dependence
Tolerance
Addiction
Pseudoaddiction
To optimize the use of opioid therapy, clinicians also must have familiarity with the principles of addiction medicine. This begins with an understanding of the definitions of physical dependence, tolerance, addiction, and pseudoaddiction.

25. Opioid Therapy and Chemical Dependency
Physical dependence
Abstinence syndrome induced by administration of an antagonist or by dose reduction
Assumed to exist after dosing for a few days but actually highly variable
Usually unimportant if abstinence avoided
Does not independently cause addiction
Physical dependence is defined solely by the occurrence of abstinence syndrome upon administration of an antagonist, cessation of therapy, or abrupt dose reduction. Physical dependence is expected, is not problematic as long as withdrawal is avoided, and differs from addiction. The words “addiction” or “addict” should never be used to describe the potential for withdrawal; the correct label in this situation is “physically dependent.”

26. Opioid Therapy and Chemical Dependency
Tolerance
Diminished drug effect from drug exposure
Varied types: associative vs pharmacologic
Tolerance to side effects is desirable
Tolerance to analgesia is seldom a problem in the clinical setting
Tolerance rarely “drives” dose escalation
Tolerance does not cause addiction
Tolerance is a complex process, defined as a reduction in a drug’s effect that is induced by exposure to the drug. Tolerance may be “associative,” due to learning, or “pharmacologic,” resulting from either pharmacodynamic or pharmacokinetic changes. In the case of analgesics, the term may apply to effects on pain or side effects. Based on clinical experience, pharmacodynamic tolerance to analgesia can result in declining efficacy. However, this appears to be an uncommon problem, because most patients’ doses stabilize for prolonged periods, and when dose escalation is needed, it typically occurs in the setting of worsening disease (and, therefore, cannot be called tolerance).

27. Opioid Therapy and Chemical Dependency
Addiction
Disease with pharmacologic, genetic, and psychosocial elements
Fundamental features
Loss of control
Compulsive use
Use despite harm
Diagnosed by observation of aberrant drug-related behavior
Addiction is a disease with a strong neurobiologic component, which is defined by the behavioral phenomena of loss of control over drug use, compulsive use, and use despite harm. Clinicians who prescribe opioids must observe drug-related behaviors and attempt to determine whether or not these phenomena are occurring. In psychiatric parlance, the label addiction is not preferred, and the term “substance-dependence disorder” is used.

28. Opioid Therapy and Chemical Dependency
Pseudoaddiction
Aberrant drug-related behaviors driven by desperation over uncontrolled pain
Reduced by improved pain control
Complexities
How aberrant can behavior be before it is inconsistent with pseudoaddiction?
Can addiction and pseudoaddiction coexist?
The term “pseudoaddiction” was coined to describe the observation that some patients with cancer demonstrate aberrant drug-related behavior, which disappears when better analgesia is provided. Use of the term has expanded over time, and it is now used to refer to a broad range of problematic behaviors that appear to be related more to desperation than to craving. The phenomenon is complex, given the observation that pseudoaddiction and addiction can coexist.

29. Opioid Therapy and Chemical Dependency
Risk of addiction: Evolving view
Acute pain: Very unlikely
Cancer pain: Very unlikely
Chronic noncancer pain:
Surveys of patients without abuse or psychopathology show rare addiction
Surveys that include patients with abuse or psychopathology show mixed results
If the definition of addiction is clear, the question can be asked: What is the risk for iatrogenic addiction in patients without a known history of addiction during opioid treatment for pain? The literature suggests that the risk is minor during the treatment of acute pain and chronic cancer pain (possibly because cancer is a disease of older patients and those who have the disease and no history of drug abuse probably lack the biologic predisposition to addiction). The literature pertaining to chronic nonmalignant pain cannot adequately clarify this question. The probability of addiction, overall, presumably is small but likely to be influenced by a number of predictors. These predictors have not yet been empirically established; based on clinical experience, they may include a personal history of substance abuse, family history of substance abuse, age, personality factors, family dynamics, and social factors.

30. Chronic Opioid Therapy in Substance Abusers
Good outcome (N = 11)
Primarily alcohol
Good family support
Membership in AA or similar groups
Bad outcome (N = 9)
Polysubstance
Poor family support
No membership in support groups
An understanding of addiction also facilitates judgments about whether patients with known histories of substance abuse can be effectively managed with long-term opioid therapy. The data are very meager. One survey suggests that some patients can be managed without difficulty, and this is supported by clinical observations. There may be predictors of responsible drug use, such as a history of alcoholism alone, good family support, and membership in peer support groups.
Dunbar SA, Katz NP. J Pain Symptom Manage. 1996;11:

31. Opioid Therapy: Monitoring Outcomes
Critical outcomes
Pain relief
Side effects
Function—physical and psychosocial
Drug-related behaviors
To effectively monitor long-term opioid therapy, clinicians should assess—and document—4 types of outcomes over time: pain relief, opioid-related side effects, physical and psychosocial functioning, and the occurrence of any aberrant drug-related behaviors.

32. Monitoring Drug-Related Behaviors
Probably more predictive of addiction
Selling prescription drugs
Forging prescriptions
Stealing or “borrowing” drugs from another person
Injecting oral formulation
Obtaining prescription drugs from nonmedical source
“Losing” prescriptions repeatedly
Probably less predictive of addiction
Aggressive complaining
Drug hoarding when symptoms are milder
Requesting specific drugs
Acquiring drugs from other medical sources
Unsanctioned dose escalation once or twice
Numerous types of aberrant drug-related behaviors have been documented. The more worrisome behaviors, such as multiple episodes of prescription “loss” despite warnings or the forging of prescriptions, presumably are more likely to be related to addiction. Studies still are needed to clarify the predictive value of these behaviors for a formal diagnosis of addiction (or substance-dependence disorder).

33. Monitoring Drug-Related Behaviors (cont.)
Probably more predictive of addiction
Concurrent abuse of related illicit drugs
Multiple dose escalations despite warnings
Repeated episodes of gross impairment or dishevelment
Probably less predictive of addiction
Unapproved use of the drug to treat another symptom
Reporting of psychic effects not intended by the clinician
Occasional impairment

34. Monitoring Aberrant Drug-Related Behaviors: 2-Step Approach
Step 1: Are there aberrant drug-related behaviors?
Step 2: If yes, are these behaviors best explained by the existence of an addiction disorder?
From the clinical perspective, an initial assessment for the occurrence of aberrant drug-related behavior is needed. This may require a variety of strategies, including communication with the pharmacy or with others, urine drug screening, or specific rules governing prescription acquisition or follow-up. If aberrant drug-related behaviors are occurring, the assessment must be broad enough to determine whether they reflect the development of an addictive disorder or some other problem. This latter point highlights the certainty that not all aberrant drug-related behavior is addiction.

35. Opioid Therapy and Chemical Dependency
Differential diagnoses of aberrant drug- related behavior
Addiction
Pseudoaddiction
Other psychiatric disorders (eg, borderline personality disorder)
Mild encephalopathy
Family disturbances
Criminal intent
Aberrant drug-related behavior may or may not reflect addiction. This implies that occurrences of these behaviors have differential diagnoses. Among the likely processes that may explain these behaviors are addiction, pseudoaddiction, personality disorders or other psychiatric disorders associated with impulsive drug use, confusional state, or problematic family dynamics. Occasionally, aberrant drug-related behavior reflects a criminal effort to divert drugs for profit.

36. Opioid Therapy and Chemical Dependency
Addressing aberrant drug-related behavior
Proactive and reactive strategies
Management principles
Know laws and regulations
Communicate
Structure therapy to match perceived risk
Assess behaviors comprehensively
Relate to addiction-medicine community
Possess a range of strategies to respond to aberrant behaviors
If patients do engage in aberrant drug-related behaviors, management may take any number of turns and should be based on knowledge of the appropriate laws and regulations and diagnostic considerations.

37. Opioid Therapy and Chemical Dependency
Addressing aberrant drug-related behavior
Strategies to respond to aberrant behaviors
Frequent visits and small quantities
Long-acting drugs with no rescue doses
Use of one pharmacy, pill bottles, no replacements or early scripts
Use of urine toxicologies
Coordination with sponsor, program, addiction medicine specialist, psychotherapist, others
In some cases, a patient engaged in aberrant drug-related behavior should discontinue therapy. Pain can be treated in other ways, or the patient can be appropriately referred. In some cases, referral for addiction treatment is appropriate. If the decision is made to continue opioid therapy, the behaviors should be controlled using one or more strategies. These strategies may include frequent visits, small refills, checking of pill bottles, the use of long-acting drugs without rescue doses, the requirement that only one pharmacy be used, the use of spot urine toxicologies (to determine whether other drugs of abuse are being taken), and the requirement for visits with a sponsor or mental health care provider. In some cases, the use of a written “contract” is a useful intervention. It should stipulate guidelines for therapy and also indicate the consequences of further aberrant drug-related behavior.

38. Opioid Therapy: Conclusions
An approach with extraordinary promise and substantial risks
An approach with clear obligations on the part of prescribers
Assessment and reassessment
Skillful drug administration
Knowledge of addiction-medicine principles
Documentation and communication
Long-term opioid therapy is an extremely valuable approach to the treatment of chronic pain. Clinicians who manage this therapy must be able to perform a careful assessment and reassessment, administer these drugs knowledgeably, monitor outcomes (including the potential for aberrant drug-related behavior), and address negative outcomes. Documentation of multiple outcomes is essential.