Opioid Addiction: No Reason to Withhold Pain Management

FACULTY:

Dustin G. Zeigler, PharmD, BCPS
Clinical Pharmacy Specialist
Hamot Medical Center
Erie, Pennsylvania

Hannah R. Howell, PharmD, BCPS
Assistant Professor
LECOM School of Pharmacy
Erie, Pennsylvania

FACULTY DISCLOSURE STATEMENTS:

Drs. Zeigler and Howell have no actual or potential conflicts of interest in relation to this program.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

Improve the understanding of opioid addiction and dependence as well as educate pharmacists about therapeutic options in treating the opioid-addicted patient.

OBJECTIVES:

At the completion of this article, the participant should be able to:

1. Define opioid addiction, dependence, and related terminology.*
2. Discuss the role of opioids in the management of chronic pain.*
3. Understand the acute and chronic management of opioid dependence with methadone and buprenorphine.*
4. Develop a plan for the patient with a history of opioid addiction and chronic pain, including treatment of acute pain.

*Also applies to pharmacy technicians.

Opioids are a class of medications indicated for the treatment of moderate to severe acute or chronic pain. Acute pain is secondary to trauma, surgery, or tissue injury with pain expected to last days to weeks. Chronic pain is defined as pain lasting greater than three to six months and can be categorized as nonmalignant or malignant. In addition, chronic pain exceeds the time normally expected for the body to overcome an injury or continues well after the injury has healed. The American Academy of Pain Management (AAPM) documented that more than half of all Americans reported experiencing recurrent or chronic pain in 2002 and that 40% of these individuals reported constant pain.¹

The management of acute and chronic pain with opioids presents many problems to health care professionals, such as concern for severe adverse effects or fear that the patient will become “addicted” or sell drugs illegally.² Concerns about addiction can be legitimate but are often unfounded, with conclusions based on preconceived ideas including the perceived overestimated prevalence of addiction as well as the potential for disciplinary action. The actual incidence of opioid addiction is difficult to accurately estimate due to the lack of definitive diagnostic criteria. One review estimated the incidence of opioid addiction to be between zero and 50% in patients with chronic nonmalignant pain and zero to 7.7% in patients with chronic cancer pain.³

Concerns for addiction or drug-seeking behavior, also known as aberrant behaviors, affect the prescribing, dispensing, and administration of opioids for pain management. Unfortunately, many patients are labeled addicts or drug seekers due to health care professionals’ lack of understanding of the definitions of addiction and the related terms of physical dependence and withdrawal. Physicians may feel uncomfortable prescribing opioids for chronic pain in patients with a history of substance abuse with legitimate acute or chronic pain. A recent national survey of state medical board members, however, showed improvement in physician knowledge about effective pain management with opioids and addiction issues.⁴ Pharmacists need to have a better understanding of how to appropriately assess addiction as well as provide recommendations for therapeutic options in patients with substance abuse issues or those receiving maintenance therapy for addiction. It is important that pharmacists are aware of the need for effective management of both acute and long-term chronic pain in all patients.

Physicians have the responsibility to prescribe opioids for a legitimate medical purpose in the usual course of professional practice. During dispensing, the pharmacist has an equal responsibility to ensure that the prescription has met all legal requirements for a legitimate medical indication and to evaluate the patient for possible addiction, abuse, diversion, and adverse effects. Through collaboration between the physician and the pharmacist, potential problems can be identified and addressed, including adjusting pain regimens due to uncontrolled pain and unwanted side effects or referring a patient to a substance abuse specialist.

Definitions

The lack of a standard definition or consensus criteria proves problematic when attempting to diagnose opioid addiction. These inconsistencies lead to confusion when assessing whether a patient on chronic opioid therapy for pain management is addicted. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines the criteria for substance dependence (TABLE 1) without specific recommendations for pain and opioid addiction. The DSM-IV definition for physical dependence includes tolerance and withdrawal—both normal physiologic responses to opioid therapy with or without the presence of addiction.⁵ Although not intended to represent guidelines for diagnosing opioid addiction, the AAPM, the American Pain Society (APS), and the American Society of Addiction Medicine (ASAM) developed terminology (TABLE 2) specific for opioid use in treating pain.⁶ Thus, physical dependence and withdrawal syndromes are not diagnostic for opioid addiction.

Table 1

DSM-IV Criteria for Substance (Opioid) Dependence and Substance Abuse

Physical Dependence

Maladaptive pattern of substance use, leading to significant impairment or distress, as manifested by at least three of the following (occurring at any time within 12 mo): 1. Tolerance:     Need for markedly increased amounts of substance         to achieve intoxification or desired effect     Markedly diminished effect with continued use of         the same amount of the substance 2. Withdrawal:     The characteristic withdrawal syndrome for the         substance, or the same (or a closely related)         substance is taken to relieve or avoid withdrawal         symptoms     The substance is often taken in larger amounts or         over a longer period than was intended     There is a persistent desire or unsuccessful efforts         to cut down or control substance abuse     A great deal of time is spent in activities necessary         to obtain the substance, use the substance, or         recover from its effects     Important social, occupational, or recreational         activities are given up or reduced because of         substance abuse     Substance use is continued despite knowledge of         having a persistent or recurrent physical or         psychological problem that is likely to have been         caused or exacerbated by the substance

Substance Abuse

Maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by at least one of the following (occurring at any time within 12 mo):     Recurrent substance use resulting in a failure to fulfill          major role obligations at work, school, or home      Recurrent substance use in situations in which it is         physically hazardous     Recurrent substance-related legal problems     Continued substance use despite having         persistent or recurrent social or interpersonal         problems caused by the effects of the substance

DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. Source: Reference 5.

Pseudoaddiction is another term that pharmacists should recognize, as it can present a dilemma when assessing aberrant behavior in patients with pain. Pseudoaddiction presents as drug-seeking behavior (such as requests for escalating doses or alternative or additional opioids) and can be difficult to differentiate from true addiction. The distinction of pseudoaddiction is that aberrant behaviors will subside once pain is adequately treated. Thus, understanding the current definitions and differences among terms (in addition to appropriate monitoring and assessment) can help health care practitioners recognize opioid addiction, abuse, and diversion.

Table 2

AAPM, APS, and ASAM Definitions Related to the Use of Opioids for the Treatment of Pain

Addiction

Primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include at least one of the following: impaired control over drug use, compulsive use, continued use despite harm, or craving.

Physical Dependence

State of adaptation that is manifested by a drug class– specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance

State of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

AAPM: American Academy of Pain Medicine; APS: American Pain Society; ASAM: American Society of Addiction Medicine. Source: Reference 6.

Aberrant Behavior

Aberrant behaviors raise the suspicion for potential addiction. Accurately identifying opioid addiction can be difficult secondary to drug-seeking behaviors. The behavioral patterns may indicate true addiction or be related to another cause, such as pseudoaddiction or tolerance. Common aberrant behaviors from patients with chronic pain who are receiving opioids are listed in TABLE 3. Behaviors from these patients are categorized as suspicious for or less predictive of addiction.^7,8 Pharmacists play an active role in resolving potential pain-related or illegal issues by communicating behaviors and assessments to the prescriber (or to law enforcement, when indicated).

Table 3

Aberrant Behaviors and Relation to Possible Addiction

Behaviors Suspicious of Addiction

Selling prescription drugs Forging prescriptions Stealing or borrowing drugs from others Injecting oral formulations Obtaining prescriptions from nonmedical sources Concurrent abuse of alcohol or illicit drugs Many unsanctioned dose escalations Multiple prescription losses Repeatedly seeking prescriptions from other clinicians or    emergency departments without informing prescriber Evidence of deterioration in ability to function at work,    at home, or socially related to opioid use Repeated resistance to changes in therapy despite clear    evidence of adverse physical or psychological effects    from opioid

Behaviors Less Predictive of Addiction

Aggressive complaining about the need for higher doses Drug hoarding during periods of reduced symptoms Requesting specific drugs Openly acquiring similar drugs from other medical    sources One or two unsanctioned dose escalations Unapproved use of the drug to treat another symptom Reporting psychiatric effects not intended by the    physician Resistance to change in therapy due to tolerable adverse    effects with expression of anxiety related to return of    severe pain

Source: References 7, 8.

Opioid Analgesics

Opioids have long been the mainstay of treatment of moderate to severe pain, both acutely and for chronic pain therapy; however, there is a delicate balance between effectively using opioids for pain relief and avoiding risk of addiction and negative outcomes that may result. Opioids can be a very safe and effective class of medications if used correctly. They should be used in combination with nonopioid or adjuvant therapies, unless contraindicated. Opioids are most effective in treating nociceptive pain and are often helpful in combination with other drug classes for neuropathic pain.

Opioids bind receptors within the central nervous system as well as supraspinal receptors to produce their analgesic effects. Activation of the mu, kappa, and delta receptors by opioids inhibits the release of neurotransmitters involved in pain. Most opioids activate the mu receptor to exert their analgesic effects. Receptor sub-types have also been identified for the three opioid receptors. Opioids have varying affinities for the receptor sub-types, resulting in variable analgesic responses from one opioid to another. For example, oxycodone appears to have a higher affinity for the kappa (2b) receptor subtype compared to the mu receptor.⁹ The variable binding of opioids to their receptors/subtypes does not confer complete cross-tolerance. When switching to a different opioid drug, a patient may experience a change in analgesic response or development of unwanted adverse effects (AEs). It is recommended to use a lower equivalent dose (typically reduce by at least one-third) when changing to another opioid.

The opioids can be classified as pure agonists, partial agonists, and mixed agonist-antagonists. Pure agonists are most commonly used to treat pain (TABLE 4). The partial agonist, buprenorphine, is commonly prescribed to treat opioid dependence or addiction, but it may also be used off-label as an analgesic. Unlike pure opioid agonists, it has a dose-ceiling effect, where the analgesic and subjective effects, such as euphoria, reach a plateau, thereby limiting abuse potential.^10,11 Buprenorphine has a high affinity for the mu and kappa receptors and slowly dissociates from the mu receptor, which increases the risk of precipitating withdrawal and reduces the analgesic effect if concomitantly administered with a pure opioid agonist. Opioid antagonists (naloxone, naltrexone) are given to reverse severe AEs and will precipitate withdrawal in a patient who is dependent on full agonists. They will not readily reverse the effects of buprenorphine due to its high affinity and slow dissociation from the opioid receptor. Mixed agonist-antagonists have predominately agonist activity as well as a clinically significant opioid antagonist component. They should never be used for management of chronic pain. Examples include pentazocine (Talwin), nalbuphine (Nubain), and butorphanol (Stadol).

Table 4
Pure Opioid Agonists
Opioid	Equianalgesic Doses	Peak (h)	Duration (h)	Half-life (h)	Usual Starting Dosea	Comments
Morphine	10 mg IM/IV/SQ 30 mg po	0.25-1 1-2	4-5 4-7	2 2	5-10 mg q4h IM 2-4 mg q5min IV 15 mg q4h po	Gold standard for comparison to other opioids
Morphine CR (MS Contin)	30 mg po	N/A	8-12	4-5	15 mg q12h po scheduled	Generics available
Morphine SR (Kadian, Oramorph)	30 mg po	N/A	Kadian: 12-24 Oramorph: 8-12	N/A N/A	15 mg q12h po scheduled
Morphine ER (Avinza)	30 mg po	N/A	24	N/A	15 mg q12h po scheduled
Oxycodone	20 mg po	1-2	4-5	3	5-10 mg q3-4h po	Available in combination with APAP or ibuprofen
Oxycodone CR (Oxycontin)	20 mg po	2-3	8-12	4-5	10 mg q12h po scheduled	Formulation provides immediate as well as slow release of drug
Hydromorphone	1.5 mg IM/IV/SQ 7.5 mg po	0.25-1 1-2	4-5 4-6	2.5 2.5	1-4 mg q4h IM 0.2 mg q5min IV 2 mg q3h po	SR no longer available
Hydrocodone	30 mg po	2	3-5	2-4	5-10 mg q3-4h po	Only available in combination with APAP, ASA, or ibuprofen
Oxymorphone (Opana)	1 mg IM/IV/SQ 10 mg po	0.25-0.5 2	3-6 4-6	2-3 7-11	1 mg q3h IM 0.5 mg q10min IV 5-10 mg q4h po	Bioavailability po = 10%
Oxymorphone ER (Opana ER)	10 mg po q12h dosing	2	12	N/A	5 mg q12h PO scheduled	Avoid alcohol with ER
Methadone	Variableb	1-2	4-6	12-15	2.5 mg q4-6h po for acute pain	Requires careful monitoring
Meperidine	300 mg IM/IV/SQ 75 mg po	0.25-0.5 1-2	2-4 4-6	3-4 3-4	50 mg q4h IM 5 mg q5min IV po not rec.	Not rec. for chronic pain; normeperidine half-life = 24-48 h; associated with CNS toxicities (seizures)
Fentanyl	100 mcg IV/IM	<0.25	1-2	3	0.05 mg q1h IM 25 mcg q1h IV
Fentanyl, mucosal lozenge (Actiq)		0.25-0.5	7	1-2	Not rec.c	Avoid in opioid naïve
Fentanyl, buccal (Fentora)		0.5-0.75	N/A	3-12	Not rec.c	Avoid in opioid naïve; lower dose if switching from Actiq
Fentanyl, transdermal (Duragesic)	25 mcg/h patch 50-100 mg oral morphine/24 h	N/A	48-72/patch	17	Not rec.c	Avoid in opioid naïve; variable absorption; diffuses from adipose after removal
IM: intramuscular; SQ: subcutaneous; APAP: acetaminophen; ASA: aspirin; CR: controlled release; ER: extended release; SR: sustained release; CNS: central nervous system; N/A: Not applicable; rec.: recommended. a Doses as needed unless otherwise specified. b Several conversion strategies have been published, including Edmonton model, Milan model, and the United Kingdom model. c Not recommended for opioid-naïve patients; dose will be based on equianalgesic conversion and clinical judgment. Source: References 33-38.

The most common AEs of opioids are nausea or vomiting, sedation, and constipation. Patients typically become tolerant to these AEs, except for constipation, after a couple days of therapy. Most patients undergoing opioid therapy require a bowel regimen, frequently a stool softener plus stimulant laxative. The fear of respiratory depression can cause some physicians to avoid choosing opioids to treat moderate to severe pain. Prescribers should be made aware that respiratory depression is uncommon with careful dose titration. Patients with underlying chronic lung disease or sleep apnea and the elderly may be at higher risk, so initiating lower doses is recommended.

While the use of fast-acting, short-duration opioids may be a very effective strategy for acute pain, it may not be the best approach when using opioids for long periods of time. Short-acting opioids produce a high initial blood level that may be associated with unfavorable side effects such as nausea or vomiting, sedation, dysphoria, and dizziness, which ultimately decrease functioning. Patients will often “clock watch” when prescribed short-acting opioids in anticipation of their pain coming back, which may also promote behavioral associations between taking a medication and pain relief and ultimately lead to aberrant behaviors and addiction.^12,13 There are many long-acting opioids available orally that have been designed to continuously provide effective relief for up to 24 hours and prevent the fluctuations in blood levels as previously described. Each option is different, and individual patients may respond better to one than another.

All opioids are metabolized in the liver. Patients with liver impairment should be closely monitored for toxicity, and dosage increases should be administered in smaller increments and less frequently than in patients with normal liver function. Morphine, meperidine, and propoxyphene have active metabolites and should therefore be used with caution or even avoided in patients with renal insufficiency. Meperidine should not be used for treating chronic long-term pain because of associated neurotoxicity (including seizures and death) due to the active metabolite normeperidine. Many pain specialists discourage meperidine use acutely as well because of its short duration and tendency to induce euphoria.¹⁴ Propoxyphene is not routinely recommended for moderate to severe pain given its lack of proven efficacy in relieving pain and the risk of euphoria and AEs.¹⁵ Morphine has active metabolites as well that may accumulate in patients with renal insufficiency and contribute to persistent nausea, hallucinations, sedation, and myoclonus.

Acute and Maintenance
Therapy for Opioid Addiction

Treating acute addiction is important, but patients with chronic pain syndromes should not go through an acute detoxification program to completely withdraw opioid therapy. They should be placed on an addiction maintenance program, which will be discussed shortly.¹⁶

If the decision to withdraw opioid therapy is made, patients will begin to experience withdrawal symptoms within a few hours up to a few days after their last dose. The acute withdrawal phase is usually not life-threatening and will generally resolve after 10 days, although pain may persist. Initial withdrawal symptoms that the patient will experience include anxiety, insomnia, yawning, and sweating; these may be followed by chills, anorexia, muscle cramps, nausea, and diarrhea. Signs include pinpoint pupils, tachycardia, hypertension, and elevated respirations and temperature. Symptomatic management includes dicyclomine, loperamide, nonsteroidal anti-inflammatory drugs (NSAIDs), and clonidine. Naltrexone, an opioid antagonist, may be given in the case of an acute overdose, especially if the patient is exhibiting signs of respiratory depression. Methadone and buprenorphine are the treatments of choice for both acute opioid withdrawal and maintenance therapy for opioid addiction.¹⁷

Methadone has long been the therapy of choice for opioid dependence and is also a very effective analgesic agent for chronic pain. Only physicians at federally licensed treatment facilities may prescribe methadone for patients as part of an addiction maintenance program, but any physician may prescribe methadone for pain.¹⁸ Unlike other opioid agonists, methadone also blocks N-methylD-aspartate (NMDA) receptors, which is likely the reason that it is more effective in the treatment of neuropathic pain than other opioids.¹⁹

The pharmacokinetics of methadone makes it a good option in treating opioid-dependent patients with chronic pain. It is well absorbed orally and has an average half-life of 15 to 25 hours, thus allowing for once-daily dosing. The duration of analgesia is much shorter; therefore, patients with acute pain require more frequent dosing, typically every four to six hours.²⁰ Some specialists will initially dose methadone every four to six hours to “load” the patient to obtain steady state levels and then decrease the frequency to every eight to 12 hours after three to five days. Methadone is extensively metabolized by the liver via CYP3A4, CYP2B6, and CYP2C19, and medications inhibiting these enzymes can increase risk of toxicity. Patients should always be instructed to watch for signs and symptoms of toxicity, including slow, shallow breathing, extreme sleepiness, and confusion or cognitive impairment. Based on methadone’s half-life, these toxicities will most likely occur between three to seven days after initiation or dose increases.

Pharmacists should be aware of the potential of methadone to prolong the QT interval. Risk factors for QT prolongation include concomitant administration of QT-prolonging or CYP3A4 inhibitors, hypokalemia, liver dysfunction, congenital long QT syndrome, and structural heart disease. Torsades de pointes is more likely with higher doses (>70 mg/day) but can occur at lower doses.

For acute detoxification, methadone 10 mg is given orally every four hours as needed, for a maximum of about 50 mg in the first 24 hours. The total dose given in the first 24 hours is administered in two divided doses the next day. This stabilization dose is decreased by 5 mg/day until the drug is withdrawn.

Maintenance of opioid addiction will typically require doses of at least 60 mg/day of methadone. Doses should be titrated in increments of 5 to 10 mg every four or five days to establish a safe and effective regimen. At low doses, methadone and buprenorphine may be equally effective, but a recent Cochrane review found that at higher doses, methadone is more effective for maintenance of opioid dependence.²¹

Buprenorphine is a partial mu-opioid agonist and, as discussed earlier, has a ceiling effect that may result in less abuse potential and a wider safety margin. It is available alone (Subutex) and in combination with naloxone (Suboxone), which has minimal absorption when taken sublingually but will block analgesic effects if administered intravenously. The combination buprenorphine-naloxone product was formulated to deter IV abuse. Side effects of buprenorphine are similar to other opioids, and mild withdrawal symptoms may occur if used in high doses or in patients who are dependent on full opioid agonists.¹⁷ The half-life of buprenorphine is approximately 37 hours with a dose-dependent duration of analgesia ranging from seven to 24 hours. Buprenorphine is metabolized by cytochrome P4503A4, and pharmacists should be aware of drug interactions that may increase or decrease levels.

Induction therapy with buprenorphine should begin 12 to 24 hours after cessation of short-acting opioid use and 24 to 48 hours after long-acting opioid use to minimize the risk of precipitating withdrawal. The dose should be slowly increased over three to seven days based on the degree of withdrawal symptoms that the patient is experiencing to a maximum daily dose of 32/8 mg. Subutex is typically used for observed induction, and nonob-served maintenance therapy is most commonly done with Suboxone. Initial doses should be given under direct observation, and further doses should be prescribed in increasing increments to avoid risk of overdose and abuse. The goal is to ensure adequate compliance and establish the minimum dosage required to eliminate withdrawal symptoms and cravings and control AEs, which for most patients will be at least 12/3 to 24/6 mg of buprenorphine-naloxone. Maintenance therapy depends on the individual patient but may last indefinitely. Frequent contact with health care professionals—including physicians, psychologists, and pharmacists—is necessary to ensure optimal outcomes.²²

Multimodal Treatment of Chronic Pain

There are multiple complex mechanisms involved in the pathophysiology of pain, and combining various analgesics with different mechanisms of action can enhance the effectiveness, and potentially decrease the toxicity, of each medication. There are conflicting data regarding improved outcomes and reduced AEs, but there is evidence of additive efficacy when combination therapy is used to treat pain.²³ Clinically, it makes sense that multiple mechanisms will be better in treating pain, similar to the reasons that multiple medications are indicated in heart failure to target different mechanisms of disease pathophysiology. However, more research is needed, and there is the added risk of polypharmacy and similar AEs, particularly central nervous system effects. For pharmacists, however, it is important to understand all of the options for treating pain in order to provide more effective pain relief and allow the use of lower doses of opioids.

Acetaminophen (APAP) has analgesic and antipyretic properties and is widely used for the treatment of mild to moderate pain both alone and in combination with a variety of other drugs, including opioids. When APAP is used with opioids for acute nociceptive pain, there is a 20% to 30% reduction in the opioid requirement secondary to enhanced analgesia.²³ Patients should titrate up to scheduled doses of up to 4 g/day divided into three or four doses for at least two weeks before APAP is considered a treatment failure.²⁴ Patients who respond to APAP may benefit from taking two 650-mg extended-release capsules every eight hours around the clock. Acetaminophen may be safely used as long-term therapy for pain relief in most patients, but the total daily dose should not exceed 4 grams, and a lower total daily dose is recommended for elderly patients, patients with hepatic or alcoholic disease, and in combination with other hepatotoxic drugs or warfarin. Based on a study published in the Journal of the American Medical Association in 2006, the American Liver Foundation has issued a recommendation that patients not exceed 3 grams per day of APAP for an extended length of time.²⁵ This is controversial and will require more studies to confirm the risks and recommended doses. For now, pharmacists should ensure that patients are aware of the APAP content of many commonly used OTC and prescription drugs, including analgesics, cough and cold products, and sleep aids.

Nonsteroidal anti-inflammatory drugs have analgesic, antipyretic, and anti-inflammatory properties and are often used to treat both acute and chronic pain. Pain of nociceptive, inflammatory, and functional origin responds well, but NSAIDs are ineffective for neuropathic pain. Studies have shown that NSAIDs have opioid-sparing effects, and the combination decreases adverse effects of opioids and provides more effective analgesia.²³

Gastrointestinal (GI) complications are well known to be associated with NSAIDs. They can range from mild complaints of nausea, abdominal pain, and diarrhea to severe complications such as bleeding, ulceration, and GI perforation or obstruction. Certain patients may be at risk of acute renal failure, congestive heart failure, and myocardial infarction when taking NSAIDs, although these AEs are much less common.

A recent study showed that the prevalence of tramadol abuse was similar to NSAID abuse and less than that of analgesics containing hydrocodone.²⁶ With respect to analgesia, tramadol likely provides more than APAP and NSAIDs but less than opioids; therefore, it may be a good choice for mild to moderate, but not severe, pain. Tramadol has a dual mechanism of action that synergistically produces analgesia from both nociceptive and neuropathic origin. It acts centrally to inhibit the reuptake of norepinephrine and serotonin and is a weak muopioid agonist. Tramadol does not have the GI or renal toxicity of NSAIDs and has less risk of respiratory depression than opioids. The most common AEs include somnolence, dizziness, headache, nausea, and constipation, and the drug may cause or worsen cognitive impairment in the elderly.²⁷ Initial dosing should be low, such as 50 mg/day, and increased every three days to a maximum of 400 mg/day divided or, in patients older than 75, 300 mg/day divided.

Medications that have analgesic properties but are currently used to treat conditions other than pain are considered adjuvant drugs. They are most often used in combination with opioid analgesics to enhance analgesic efficacy, especially in conditions with a primarily neuropathic component. Through a variety of mechanisms, adjuvant drugs decrease peripheral and central stimulations that are interpreted centrally as pain. The most commonly recommended adjuvant medications include tricyclic and other antidepressants and anticonvulsants, specifically gabapentin and pregabalin. Serotonin norepinephrine reup-take inhibitors can be used in patients who cannot tolerate tricyclic antidepressants or in whom their use is not recommended (i.e., the elderly).

Pain Management in a
Recovering Opioid-Dependent Patient

Managing patients with a current or past opioid addiction can be extremely difficult for a variety of reasons, including physician fears, tolerance, and the presence of a psychiatric disorder.¹⁶ The short-term goal for these patients is a reduction or resolution of pain. Secondary is the desire to maintain physical and social functioning. Nonpharmacologic treatments, nerve blocks, physical therapy, surgery, relaxation techniques, and nonopioids should be used for treating pain whenever possible, but opioids and other psychotropic medications may be required when effective pain management is not achieved by these methods.

Patients on methadone or buprenorphine (or any chronic opioid therapy) may develop a phenomenon known as hyperalgesia. Although the entire mechanism of development is not completely understood, patients will have increased sensitivity to pain and decreased responsiveness to opioids.^28-30 Possible methods to manage hyperalgesia include prescribing pharmacologic and/or nonpharmacologic adjuvant therapy to prevent rapid escalation of the opioid dose and opioid rotation, which is a gradual switch to an alternate opioid. Lowering the dose of the currently prescribed opioid may also improve pain management in the setting of hyperalgesia.

Several adjustments are required for treating pain in patients on maintenance methadone therapy. Typically, these patients are on once-daily regimens and, as previously discussed, the analgesic effects only last four to six hours. In addition, these patients will not have the predicted analgesic response due to the chronic use of methadone. If patients are hospitalized with acute pain (i.e., postoperative), the first step is to verify the patient’s methadone dose with the methadone maintenance program. The patient’s maintenance methadone dose should be continued with the addition of a short-acting opioid agonist, such as morphine, to control acute pain.³¹ The use of IV or patient-controlled analgesia (PCA) may be appropriate for the acute postoperative period with subsequent conversion to a short-acting oral opioid. Scheduled, rather than as-needed, doses of opioids may be required for the acute period (24-28 hours) following surgery. Adjustments to pain medications should be based on analgesia and/or AEs. For a patient with chronic pain, dividing the daily methadone dose every eight or 12 hours may provide better pain control. The total daily dose may need to be increased due to tolerance. A short-acting opioid can be used on an as-needed basis for breakthrough pain, and the use of nonopioid or adjuvant therapy is recommended. When the patient is discharged from the hospital, the maintenance program should be notified of changes or additions to therapy.

There are also many options to consider when managing pain in patients on buprenorphine. The pharmacology of buprenorphine must be considered when developing a therapeutic plan. Adding a pure opioid agonist to buprenorphine may not produce expected analgesic response. This is due to buprenorphine’s high affinity for the mu receptor and resulting competition or displacement of the pure agonist from the receptor. Due to the variable binding and dissociation, monitoring of severe AEs (i.e., respiratory depression) is warranted with such a combination. When treating acute pain, the daily buprenorphine dose can be divided every six to eight hours to take advantage of its pharmcodynamic properties. Higher doses of buprenorphine may be required to treat pain in patients on chronic therapy. Another option includes discontinuing buprenorphine and prescribing a short-acting pure opioid agonist, preferably on a routine basis.³¹ When the acute pain has resolved, buprenorphine can be reinitiated via an induction protocol and the pure opioid agonist can be discontinued. Alternatively, for hospitalized patients, methadone 30 to 40 mg/day can be substituted for buprenorphine with minimal risk for withdrawal.³² The dose can be titrated as needed for withdrawal or pain symptoms. Methadone should be increased by 5 to 10 mg/day every three to five days to avoid accumulation. The total daily dose may be divided every eight or 12 hours for better pain control, and a short-acting pure opioid agonist can be utilized for breakthrough pain. Once the pain has resolved, the methadone and pure opioid agonist can be discontinued and a buprenorphine induction protocol can be initiated. In cases of buprenorphine-naloxone or another mixed agonist-antagonist, the opioid agonist-antagonist should be discontinued during treatment of acute pain. For elective surgeries with expected moderate to severe pain requiring opioid therapy, the mixed agonist-antagonist should be discontinued two or three days prior to surgery. This will prevent precipitation of withdrawal with administration of a pure opioid agonist. The agonist-antagonist therapy can be reinitiated once pure opioid agonist therapy is no longer needed. The half-life and duration of the pure agonist must be considered when restarting the mixed agonist-antagonist.

Conclusion

It is important to develop effective mechanisms of monitoring, careful documentation, and effective communication when treating pain in patients with a history of opioid addiction. A multidisciplinary approach with the collaboration of health care professionals—including a substance abuse specialist, pain specialist, mental health professional, and pharmacist—is recommended. It may be helpful to include close family members in the treatment process to provide the patient with an adequate support system. Consultation with a mental health professional can ease underlying psychiatric illnesses, such as depression and anxiety. Keeping patients informed of the goals and expectations of therapy will reduce stress and anxiety. In addition, written pain contracts between the patient and health care team provide structure and enhance compliance to the treatment plan. These documents should highlight expectations and concerns of both the patient and providers. The contracts can include agreements or consent to test periodic urine samples, take pill counts, and assess behaviors that will violate the contract and require discontinuing opioid treatment.

For the health care professional, documentation plays a vital role in reducing the fears of disciplinary action when prescribing opioids for a legitimate indication. This includes charting the medical diagnosis with results of diagnostic studies, substance abuse history, treatment plan, and response to therapy, as well as reasons for changing therapy or adding another controlled substance. The name and address of the patient prescribed the opioid, name of the drug, quantity (also number of refills), and dosage form should also be noted. Documentation of monitoring pain symptoms (improvement or worsening, indicating change in treatment regimen), medication use, and AEs is recommended. Prescribing only the amount of medication sufficient until the patient’s next appointment is effective monitoring of medication use.

Pharmacists in any health care setting should recognize opportunities to impact the management of patients with pain. They can play an active role in monitoring AEs and analgesic response, identifying drug interactions, and assessing aberrant behaviors. Pharmacists can have a positive impact by recognizing the complicated pharmacologic issues of managing pain in patients with a history of opioid abuse or risk factors for addiction.

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