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10 Articles in Volume 7, Issue #7
Burning Mouth Syndrome
Chronic Pain Program in a Primary Care Setting
Chronic Persistent Pain Can Kill
Education and Exercise Program for Chronic Pain Patients
Managing Pain in Intensive Care Units
Oxycodone to Oxymorphone Metabolism
Patulous Eustachian Tube: Part 1
Rational, Emotive, Ethical Approaches to Bio-psychosocial Pain Care
Smoking and Aberrant Behavior in Chronic Pain Patients
Structuring Opioid Therapy

Structuring Opioid Therapy

Patient stratification for certain characteristics can minimize the risk of sleep apnea and respiratory depression.

As analgesics, opioids are without equal, cutting most types of pain, on average, by at least 30 percent.1 However, opioids are not a panacea and confer significant risks to patients in addition to benefits. Opioid therapy for chronic pain has the best chance for success when treating clinicians take steps to maximize safety and support appropriate use.

Three common sources of risk are 1) patient difficulty in managing opioid use, 2) the potential worsening of sleep-disordered breathing, and 3) dosing that leads to respiratory depression—particularly when methadone is prescribed or consumed for pain by people unfamiliar with its special properties.

Opioid-use Disorders

The neurobiological disease of addiction is not synonymous with drug abuse, which can have numerous causes; however, any problem a patient manifests in managing opioid intake is likely to damage the integrity of pain therapy if not dealt a swift and suitable solution. Because true opioid addiction affects only about 1% of the general population2 and up to perhaps 5% of the chronic-pain population (see Figure 1), it is clear that most people who take medications for pain will not become addicted to them. Difficulties in managing opioid intake that stem from causes other than addiction are common, however. Figure 1 illustrates the relationships and frequency of aberrant behavior, abuse, and addiction documented in the author’s pain practice. Although 40% of the patients displayed at least one aberrant behavior associated with medication misuse within one year, only 20% of the patients met a diagnosis of drug abuse and still fewer (2-5%) met the diagnosis for opioid addiction. It could be said that all addicted people, then, are abusers, but not all abusers are addicted. Furthermore, aberrant behavior only rises to the level of drug abuse about half the time and is even more seldom a sign of the disease of addiction.

These delineations help the clinician choose the right monitoring guidelines because, as motivations for abuse differ, so will the clinician’s response in intensifying monitoring measures. Drug abuse and the comorbid conditions that sometimes give rise to it must be addressed in tandem with pain therapy or the pain therapy has little chance of success.

Management takes place by initiating a structure for prescribing opioids that contains the following components:

  1. All patients to be prescribed opioids for pain must undergo assessment prior to beginning opioid therapy to determine their level of risk for drug abuse.
  2. Once the assessment is complete, patients should be stratified according to risk level.
  3. Patients are then monitored according to risk level using “proactive," rather than “reactive," strategies.3
  4. Patients’ treatment plans and goals are reassessed frequently, adjusted as needed, and documented thoroughly.

Assessment and Risk Stratification

Several opioid-specific assessments are available for clinical use, including the Opioid Risk Tool (ORT)4 and the Screener and Opioid Assessment for People with Pain (SOAPP),5 as well as several non-opioid-specific tools that can be adapted. Tools to assess for current or potential substance abuse utilize risk factors for abuse such as age, personal or family histories of substance abuse, past sexual abuse, the presence of complicating mental disorders, smoking status, and prior problems with the law, to name a few. Assessment for drug-abuse potential should be routine for every patient seeking opioid therapy to treat chronic pain. Opioid-specific tools that have been validated in pain populations and that have predictive value are preferred, but clinicians must choose a template that fits with their own clinical situation that considers the time available, access to expertise, and preference for self-administered or interview tools. Perhaps more important than the choice of tools is the consistent action of performing and thoroughly documenting some type of assessment that combines the best available assortment of questions supported by the literature and clinical experience.

Assessing patients gives clinicians the information needed to stratify patients according to abuse risk; typically, abuse risk can be classified as high, moderate, or low. Low-risk patients, for example, tend to have mild-to-moderate pain, an absence of complicating mental disorders and substance-abuse histories, and stronger self esteem and coping skills compared to higher risk patients. The risk increases to moderate when life stress is significant, pain is intractable and social support systems are weak. High-risk patients are marked by major mental health disorders, family and personal histories of substance abuse, histories of sexual and physical abuse (particularly as children), status as smokers, and age less than 50 years.

Patients are monitored according to risk category, with monitoring measures intensifying as the risk rises. See Table 1 (page 14) for a suggested hierarchy of monitoring measures based on risk level. For all patients, clinicians should carefully document the ‘Four As’: analgesia, activities of daily living, adverse events, and aberrant drug taking.6 When abuse risk rises to moderate or high, clinicians should schedule clinic visits more frequently with prescription refills contingent on attendance and, consider as needed, such actions as limiting or eliminating rapid-onset analgesics (ROAs), referring for addiction/psychiatric evaluation, or requiring increased compliance testing via urine or other drug screening.7 When abuse risk is high, many of the most stringent measures, such as referral for treatment of mental health or substance disorders, become mandatory and consideration should be given to appointing a third party, such as a relative, to control and administer medication. In addition, clinicians should limit or eliminate ROAs for the highest-risk patients and also consider limiting short-acting opioids (SAOs). Compliance testing via urine or blood should be intensified, and some screenings should be unanticipated by the patient. When a patient’s risk for abuse appears unclear, it is preferable to monitor that patient more strictly than is necessary for a time than to underestimate the hazards of drug abuse. Monitoring measures can always be adjusted downward once an acceptable level of compliance has been established.

Choosing the Right Opioid Formulation

Patients’ vulnerabilities for opioid abuse are conferred by genetics, environment, and drug properties. The pharmacology of an opioid formulation, though a weaker factor in abuse potential than environmental or genetic influences, is still a significant contributor to abuse risk. Therefore, the drug’s pharmacokinetics, lipophilicity, and attractiveness in terms of abuse potential—particularly to patients with histories of drug abuse—must all be taken into consideration when choosing treatment regimens.

Figure 1. Source: Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med. 2005 Nov-Dec; 6 (6):432-42.

Long-acting opioids (LAOs) are frequently touted as being preventative of abuse because they steady blood serum levels, help patients sleep through the night, and eliminate the need for frequent servings of medication. This last characteristic is likely a boon for patients with risks for abuse because it eliminates the need for frequent administration, thus discouraging binge behavior. However, LAOs with sustained-release formulations can be altered to release their sustained-action analgesia all at once and are prized by habitual abusers of opioids as attractive choices.8 SAOs have long been thought to be more abuse friendly than LAOs; however, little evidence supports this thesis. Although short-acting hydrocodone formulations are the most commonly abused opioids, that prevalence may be due not to their pharmacology but to their Schedule III classification, which increases the ease with which many clinicians prescribe them. ROAs such as transmucosal fentanyl are apt to deliver the quick peak effect sought by drug abusers. Fentanyl is highly lipophilic, quickly crossing the blood-brain barrier and gaining quick access to the central nervous system. RO opioids could cause problems for patients prone to abusing opioids, but every patient is an individual, and the most important criterion in choosing medication is likely to be avoiding drugs with properties similar to drugs abused in the past.

Match Monitoring to the Patient’s Risk of Drug Abuse
Low Risk (Routine) Moderate Risk High Risk
Pain assessment
Substance-abuse assessment
Informed consent
Signed treatment agreement
Regular follow-up visits, prescriptions
Initial prescription database check
Medical reports
Initial urine drug screening
No consultation required
Medication type, unrestricted
Document “Four As"
Document patient-provider interactions
Monthly or biweekly visits
Monthly or biweekly prescriptions
Regular prescription database check
Seek verification from patient’s family
Random urine drug screening
Consider comorbid mental disease
Consider psychiatric/addiction/pain evaluation
Consider medication counts
Consider limiting rapid-onset analgesics
Weekly visits
Weekly prescriptions (on attendance)
Quarterly prescription database check
Third-party administration
Urine drug screening: scheduled and random
Consider blood screenings
Psychiatric/addiction evaluation required
Consider pain specialist evaluation
Limit rapid-onset analgesics
Consider limiting short-acting opioids
Source: Webster LR, Dove B. Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners. 1st ed. North Branch, MN: Sunrise River Press; 2007.

Emerging Treatment Options

Research is advancing in the area of abuse resistance (opioids with physical barriers to adulteration) and abuse deterrence (opioids incorporating a pharmacology that lessens their abuse potential). One approach is to incorporate an opioid antagonist, such as naltrexone, along with the therapeutic agonist agent. Taken as directed, the opioid is absorbed as intended with little or no absorption of the antagonist. However, crushing, damaging, dissolving, mixing with alcohol, or otherwise manipulating the product will release the antagonist at doses sufficient to antagonize the opioid effects. Figure 2 shows two examples of agonist/antagonist combinations. Capsule A houses a naltrexone nucleus within an opioid matrix that only releases the naltrexone if the formulation is altered. Capsule B holds polymer-coated beads, some containing naltrexone and others containing an opioid. The beads look identical, but the opioid is released by normal pH changes of the gastrointestinal tract, while the thicker polymer coating of the naltrexone bead is not pH responsive and only permits release of the agent if the formulation is altered.

There are many other examples of forthcoming agents designed to resist or deter abuse. These include gel caps containing sustained-release opioids that resist alteration, formulations that release aversive secondary irritants when altered, and opioids containing ultra-low-dose antagonists that have demonstrated some success in slowing the development of tolerance and physical dependence.7 All prescribers of opioids should keep current with research in the area of opioid abuse prevention to give their patients the best opportunities for good clinical outcomes.

The Danger of Sleep-Disordered Breathing

Chronic pain and sleep dysfunction are closely associated for many reasons, but few studies have assessed the effect of opioids and other medications on sleep in patients with pain. Now, a growing body of literature is beginning to document a high prevalence of sleep-disordered breathing in pain patients treated with opioids. Farney and colleagues, who run the Intermountain Sleep Disorders Center at LDS Hospital in Salt Lake City, began to notice something peculiar in patients on chronic opioid therapy referred to their sleep lab. As a result of these observations, the team issued a case series report of three patients on sustained-release opioids who demonstrated distinct patterns of sleep-disordered breathing, including ataxic breathing, central apneas, sustained hypoxemia, and unusually prolonged obstructive “hypopneas" secondary to delayed arousal responses9 (see Table 2 for definitions related to sleep-disordered breathing).

More recent research has demonstrated a high prevalence (75%) of central and obstructive sleep apneas in chronic pain patients treated with opioids (Figure 3).10 Furthermore, a direct relation between central sleep apnea and doses of methadone and benzodiazepines was found. The findings can be summarized as follows:

  • Use of methadone was associated with an 89% increase in the apnea-hypopnea index (AHI), a measure of overall severity of sleep apnea.
  • Use of methadone was associated with a 113% increase in the central apnea index (CAI), a measure of the number of central sleep apneas per hour of sleep.
    Use of benzodiazepines was associated with a 69% increase in the CAI.

These and similar findings call for increased vigilance from pain practitioners in assessing patients for risk, diagnosing and treating sleep-disordered breathing, and monitoring response when administering medications for pain.

Of further interest are the idiosyncratic findings associated with sleep disorders combined with pain when compared to sleep apnea in the general population. In the study by Farney and colleagues, oxygen desaturations were more severe and respiratory disturbances were longer during NREM sleep compared to REM sleep, in contrast to what is usually observed in subjects with obstructive sleep apnea. And in a study of opioid-treated patients with central sleep apnea, no pattern was found of Cheyne–Stokes respiration, which is characterized by a crescendo–decrescendo pattern of tidal volume.10 The reasons are not yet clear why these variations from the norm were observed in opioid-treated pain patients.

Minimizing Risk for Sleep Apnea

Steps to minimize the risk begin with patient assessment and stratification followed by appropriate therapeutic interventions. It is advisable to order polysomnographies on patients who present a high risk for sleep apneas. Characteristics for at-risk patients follow:

  • A high body mass index (BMI >30)
  • Is taking a high opioid dose, particularly when prescribed long term
  • Is prescribed methadone
  • Is prescribed benzodiazepines in combination with methadone

Figure 2.

A plan instituted at Lifetree Pain Clinic—to assess for and manage sleep-disordered breathing in patients on around-the-clock opioids—calls for the following risk stratification after screening:

  • Level 1 (highest risk): CAI > 5 events per hour; AHI > 30 events per hour
  • Level 2 (moderate risk): AHI > 5 events per hour
  • Level 3 (lowest risk): AHI < 5 events/hour

Patients whose polysomnographies reveal abnormal sleep architecture should be provided with therapeutic interventions. Continuous or bilateral positive airway pressure (CPAP or BPAP) should be considered. More research into therapeutic interventions is needed, and several studies are underway to determine the best treatment for opioid-related sleep apnea.

An additional sleep study should take place with every major dose change, and patients who demonstrate sleep-disordered breathing but poor compliance with treatment, such as escalation of doses without authorization, should be subject to lowered doses or removal from opioid therapy if compliance cannot be established.

Figure 3.

The Need to Maximize Safety in Methadone for Pain

Increases in mortality associated with methadone have been reported in recent years, paralleling methadone’s rising popularity as a drug to treat chronic pain.11-12 Methadone’s relative increase in poisoning deaths outpaces that of all other drugs; methadone was mentioned in 13% of all U.S. drug-related deaths in 2004, up from 4% just 5 years earlier.13

The increase in deaths associated with methadone may be driven by several factors stemming from patient or clinician error. Patients may overuse their medication in an effort to maximize pain control or may be mixing methadone with unauthorized substances such as street drugs, alcohol, benzodiazepines, or other medications. It is vital when counseling patients to ensure that they understand the necessity of complying with all medical direction and perceive the danger of escalating their own doses of methadone.

Because methadone has a long, variable elimination half-life that averages 20 to 35 hours with a range of 5 to 130 hours,14 clinicians may be underestimating the potential for toxic buildup leading to respiratory depression. Sources of clinician error could include initiating methadone at too high a dose, escalating doses too rapidly, or placing misguided faith in published conversion tables when switching from another opioid to methadone. Further contributory risks are coming to light, such as those conferred by sleep apnea and concomitant benzodiazepines.10

Table 3. Suggested Guidelines to Initiate Methadone for Pain
  Starting Methadone Dose
Total Daily Morphine Healthy Adult Adult with chronic illness or >70 yrs
Opioid naive 5mg tid 2.5mg bid
60mg-100mg 5mg tid 5mg bid
>100mg 5mg qid 5mg bid
Source: Webster LR. Methadone-Related Deaths, J of Opioid Mgmt, October 2006

When Structuring Methadone

When initiating methadone for pain, it is best to make several assumptions: that patients present a high degree of non-adherence to medical direction, that tolerance to respiratory effects is less complete than that which occurs with other opioids, and that little or no cross-tolerance has occurred with any other opioids patients may be taking. Designating patients as opioid naïve is the safest course to take until more research is available to clarify specific risk factors for methadone mortality.

See Table 3 for a suggested approach to initiating methadone therapy.11 These guidelines are even more conservative than the ones outlined by the FDA in a recent public health advisory that warned of dangers associated with methadone.15 Dose adjustments should occur no more frequently than weekly. If the patient is already on a regimen of opioids when methadone is initiated, the current medication should be adjusted downward slowly, while methadone should be simultaneously titrated upward slowly. If the patient is opioid naïve, a short-acting agent may be necessary to control pain during the period when a safe, effective dose of methadone is being determined. The goal of low initiation and slow titration is to ensure patient safety and to give methadone pain therapy a greater chance for success.


Patients to be treated with chronic opioid therapy should be assessed for risks associated with opioid use. Patient stratification as to potential for abuse or for characteristics associated with sleep apnea can be used to structure treatment. Methadone properties should be well understood, and patients should be counseled as to the necessity of complete compliance with medical direction. The risk assumed by any patient can change over time and requires continuous reassessment, which may reveal the need for therapy modifications to optimize treatment.


Technical writing assistance provided by Beth Dove of Lifetree Clinical Research and Pain Clinic.

Last updated on: February 26, 2013
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