US Pharm. 2012;37(5):31-35.
The last several decades have seen a significant rise in the use of
opioid medications. A recent study demonstrated an equally significant
increase in the number of drug overdose deaths, with opioid medications
suspected in 14,800 deaths in 2008 and representing approximately 73% of
all prescription drug overdose deaths.1 There is also a likely increase in the number of patients developing opioid dependence.
SUBSTANCE ABUSE, ADDICTION, AND DEPENDENCE
Substance abuse, as described by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) (DSM-IV), is a maladaptive pattern of substance use that leads to clinically significant impairment or distress. DSM-IV criteria for substance abuse appear in TABLE 1.2 Addiction is characterized by compulsive drug use and drug seeking despite adverse social, psychological, and/or physical consequences.3 Physical dependence is a state that develops during regular drug use in which a withdrawal syndrome results upon drug cessation.3 Dependence differs from addiction and substance abuse in that it occurs as a result of normal adaptations to chronic drug exposure.
Over the last two decades, there has been a steady increase in the
total number of opioid prescriptions. From 1991 to 2010 the number of
opioid prescriptions increased sixfold, from 30 million to 180 million
prescriptions.4 Concurrent with this growth in opioid
prescriptions has been an increase in diversion and nonmedical opioid
use. In 2009, an estimated 5.3 million persons were taking pain
relievers for nonmedical uses.4 In 2010, nearly 5% of the U.S. population aged 12 years and older was taking an opioid pain reliever for nonmedical purposes.1
In the U.S. in 2007, nearly 100 people died each day from a drug overdose.1 According to the CDC, death rates from opioid overdoses have more than tripled since 1999.5 Increased opioid use has contributed to the increase in overdose-related deaths (FIGURE 1). Opioid pain relievers currently account for more overdose deaths than heroin and cocaine combined.1
Not everyone receiving opioids will develop an addiction; however,
certain biological and environmental risk factors increase the
likelihood of substance abuse. Males are 1.5 times more likely to become
dependent on opioids.2 Psychological conditions such as
depression, anxiety, attention-deficit/hyperactivity disorder or
attention-deficit disorder, and posttraumatic stress disorder confer an
increased risk of addiction, as the sufferer may use drugs to cope with
the condition.6 Peer pressure and lack of family involvement are environmental risk factors that may predispose a person to substance abuse.6
Opioids are safe and effective for pain management when taken as
prescribed. However, these drugs can cause severe adverse
effects—including drowsiness, slurred speech, confusion, respiratory
depression, and even death—in cases of abuse.2 Opioid
withdrawal symptoms may occur following dose reduction in chronic users
or upon abrupt cessation. The onset of withdrawal symptoms varies
depending upon the specific opioid used and occurs from hours to days
after cessation.2,7 For example, with heroin, withdrawal
symptoms can occur within 1 to 3 hours, while with methadone they may
not appear for 3 to 5 days. Withdrawal symptoms are listed in TABLE 2.
An important concept in opioid dependence is the pharmacology
associated with these medications. Three major types of opioid receptors
are involved in analgesia: mu, delta, and kappa receptors.8
Activation of mu receptors produces analgesia, sedation, euphoria,
respiratory depression, constipation, and physical dependence.
Activation of kappa receptors produces mild analgesia and less
respiratory depression; delta receptor activation may induce analgesia
with fewer adverse effects. Opioids have varying effects on these
receptors. Agonist agents produce analgesia, whereas antagonists
Opioid classification is determined by receptor activity. Classes
include full agonists, partial agonists, agonist-antagonists, and
antagonists.8 Full agonists (morphine, fentanyl, oxycodone,
hydrocodone, methadone) activate mu receptors, producing analgesia.
Buprenorphine—a partial agonist—has a strong affinity for mu receptors,
but produces mild analgesia that is accompanied by an analgesic ceiling
effect. The mu receptors’ strong affinity may displace other mu receptor
agonists. Agonist-antagonists (pentazocine, butorphanol, nalbuphine)
typically act as antagonists on mu receptors and as agonists on kappa
receptors, leading to milder analgesic effects with fewer adverse
effects. Caution should be exercised in the use of partial agonists or
agonist-antagonists in patients currently receiving full agonists
because opioid withdrawal syndrome could be precipitated. The
antagonists naloxone and naltrexone block mu and kappa receptor
activation, preventing analgesia; they are used mostly as reversal
The treatment of opioid dependence includes several modalities.
Office-based or specialized treatment centers are the core component of
the treatment of opioid dependence.9-11 Long-term treatment
may include maintenance therapy with opioid agonists or antagonists.
Additional treatment options include abstinence-based treatment
approaches with nonpharmacologic adjunctive treatment (e.g., Narcotics
Anonymous). The following are pharmacologic agents used for treatment (TABLE 3).
Methadone: A synthetically derived opioid,
methadone is listed as a Schedule II medication by the Controlled
Substances Act. Methadone is a mu receptor agonist with additional N-methyl-D-aspartate receptor antagonism.8
Its half-life ranges from 8 to 59 hours with a much shorter analgesic
effect, necessitating thrice-daily dosing for analgesia. Dosing for
maintenance therapy is typically once daily. Methadone’s long half-life
allows it to stay bound to mu receptors, preventing withdrawal symptoms
while keeping additional opioids from binding to the receptor, thereby
blocking euphoria. Methadone is metabolized through the CYP450 system.
Drug interactions should be anticipated and evaluated appropriately.12
Buprenorphine: Buprenorphine is a partial mu receptor agonist.8
It has a strong mu receptor affinity, but low analgesic potential
because of its ceiling or plateau effect. This effect also may render
buprenorphine overdoses safer compared with methadone. The role of
buprenorphine in maintenance therapy is due to its strong mu receptor
affinity, which ultimately blocks additional opioids from binding to the
receptor. Buprenorphine produces sufficient agonist effects to allow
discontinuation of the abused opioids without causing withdrawal
effects. If buprenorphine is given to a patient while opioids are
coupled to mu receptors, it may displace other opioids, potentially
leading to withdrawal symptoms. Because of this potential, buprenorphine
or buprenorphine combination therapy should be initiated only after
opioid withdrawal symptoms become apparent or under direct medical
Naloxone/Naltrexone: Naloxone and naltrexone are competitive antagonists with high affinity to mu and kappa receptors.8
Use of these agents leads to a rapid displacement of opioids from
receptors, causing withdrawal symptoms; therefore, the patient should be
opioid free at the time of initiation to avoid inducing acute
withdrawal symptoms. These medications are used as abuse deterrents.
Naloxone has low oral bioavailability and is rapidly inactivated because
of first-pass metabolism. It typically is combined with buprenorphine
(Suboxone) to prevent abuse through crushing and parenteral injection.
Parenteral administration of naloxone has a rapid onset with full
receptor reversal, and the drug is used primarily for acute opioid
reversal in overdose settings. Naltrexone has higher bioavailability,
permitting oral use, and is available as an intramuscular depot
Clonidine: Clonidine is a centrally acting
alpha-2 agonist that suppresses noradrenergic activity. Opioid use also
produces noradrenergic inhibition, and an increase in noradrenergic
activity is seen during phases of opioid withdrawal. Clonidine replaces
noradrenergic inhibition previously provided by opioids while
attenuating withdrawal symptoms.9,13 Clonidine may be used
for acute opioid withdrawal and the transition to long-term maintenance
therapy. Hypotension and sedation may limit the use of clonidine.
Levo-Alpha-Acetyl-Methadol: This agent, an
opioid antagonist, was removed from the U.S. market in 2003 based on
reports of life-threatening ventricular rhythm disorders.10
History and Regulations
Methadone replacement, the first treatment for opioid dependence, has been available since the 1960s.14
Concerns regarding methadone diversion by both patients and physicians
led to the Narcotic Addiction Treatment Act (NATA) of 1974. NATA
authorized the Drug Enforcement Administration (DEA) to register with
the federal government any physician wishing to prescribe methadone for
detoxification or maintenance therapy.15 Although NATA helped control methadone diversion, it ultimately limited treatment options for many individuals.
In the U.S., the treatment of opioid dependence with opioid medications is governed by Federal Regulation 42 CFR Part 8.16
Methadone for opioid dependence is restricted to certified opioid
treatment programs (OTPs) or licensed inpatient hospital detoxification
units. Methadone may be used to treat pain; however, a prescriber may
not use the 40-mg tablets for this indication. The 40-mg formulation is
indicated only for opioid dependence detoxification and maintenance
therapy and is distributed only to hospitals and facilities authorized
to treat opioid dependence.10 To lessen the incidence of
abuse by IV injection, only the oral formulation of methadone is
permitted for use in opioid dependence. Practitioners wishing to use
methadone for maintenance and detoxification must obtain a separate DEA
registration number. In addition to federal regulations, individual
state laws may mandate other restrictions or requirements for methadone
treatment facilities. Patients are generally required to pick up doses
of methadone at the OTP on a daily basis, although under some
circumstances (e.g., patient compliance) small quantities of take-home
methadone doses may be dispensed.
In May 2001, the Department of Health and Human Services (DHHS)
announced a new system for methadone maintenance-treatment monitoring
and regulation. Oversight of these programs shifted from the FDA to the
Substance Abuse and Mental Health Services Administration’s (SAMHSA)
Center for Substance Abuse Treatment (CSAT). SAMHSA, a branch of the
DHHS, was established in 1992. Congress directed SAMHSA to target
substance abuse and mental health disorders in those people most in
need. Under this system, programs must be accredited by CSAT-approved
accreditation bodies and the designated state authority.17 This system is based upon best-practice guidelines and permits less variability in the standard of care provided.
The restriction of methadone to OTPs and specialized treatment
centers may cause patients not wishing others to know that they attend a
methadone clinic for maintenance to limit their treatment. This concern
led to the development of the Drug Addiction Treatment Act (DATA) of
2000, which was specifically designed to provide alternative treatment
options for opioid dependence. DATA allows physicians who meet certain
qualifications to prescribe Schedule III, IV, and V medications
(primarily buprenorphine) approved for the treatment of opioid
dependence to patients needing treatment for their addiction. Physicians
must also indicate that they have the ability to refer patients to
appropriate counseling if needed. Originally, DATA permitted a physician
to treat up to 30 patients at any given time, but this changed in 2007,
so that after 1 year a physician may request permission to treat up to
100 patients.17 Physicians who meet qualifications to
prescribe buprenorphine receive a special DEA number beginning with an
X. For the medication to be dispensed by a pharmacy, this number must
appear on every prescription.10
Several regulations related to the prescribing and administration of
medications used to treat opioid dependence have developed over time.
Practitioners who are not specifically registered to conduct a narcotics
treatment program may administer—but not prescribe—narcotics to a
patient in acute withdrawal while making necessary referrals.18
Unlicensed practitioners may provide methadone for dependence or
withdrawal for a maximum of 3 days while working on referral to a
Methadone and buprenorphine are the most common maintenance therapy
options. With methadone, an initial dose is given and further dosing is
titrated based upon withdrawal symptoms experienced 2 to 4 hours after
administration. Methadone maintenance treatment typically lasts 12
months or up to 2 years, and doses generally range from 80 to 120 mg
Maintenance therapy with buprenorphine is classified into three
phases: induction, stabilization, and maintenance. The goal of the induction phase
is to find the smallest dose of buprenorphine that allows the patient
to discontinue opioids without experiencing withdrawal symptoms, usually
over 3 to 5 days. In general, buprenorphine should be initiated 12 to
24 hours after short-acting opioids and 24 to 48 hours after long-acting
opioids. It is recommended that the patient be observed during initial
dosing since buprenorphine may induce withdrawal symptoms. The stabilization phase
begins when a patient no longer experiences withdrawal symptoms. Dose
adjustments may be necessary to prevent further cravings and minimize
side effects. Most patients remain in this phase for 1 to 2 months, and
the need for counseling and ancillary services should be assessed. The
final treatment phase, maintenance, is also the longest phase and
may last from months to years, depending upon the patient. The goal of
maintenance is to identify social and family issues associated with the
patient’s use of opioids. The physician should continue patient
monitoring during this phase while devising a plan in anticipation of
DATA, as previously described, enables physicians to offer
office-based treatment of opioid dependence using buprenorphine as
monotherapy or combined therapy. This model involves coordination of
care services in a physician’s office, versus the traditional OTP at a
specific treatment facility and with limited physician involvement.
Office-based treatment using buprenorphine increases treatment
availability for patients while allowing services to be tailored to the
patient’s needs. It also preserves the patient’s autonomy so that it is
not necessary to visit a methadone clinic. In determining whether this
treatment approach is best for a given patient, the practitioner must
take into consideration patient-specific characteristics, physician
training and experience, and regulatory issues. Patients best suited for
office-based treatment include those who have been enrolled in a
maintenance program for 1 to 5 years, are clinically stable with no
evidence of illicit drug use, have no untreated psychiatric conditions,
have stable financial support, are compliant with treatment, and have no
history of relapse.11
The use of opioid medications has been on the rise over the last
several decades. There is also a likely increase in the number of
patients developing opioid dependence. For these reasons, it is
important for pharmacists to be educated on this class of medications
and fully understand their proper use and administration. When used for
maintenance treatment of opioid dependence, methadone may be prescribed
and administered only in an OTP accredited by SAMHSA-CSAT. The
40-mg formulation of methadone is indicated only for the detoxification
and maintenance treatment of opioid dependence. For buprenorphine to be
dispensed by the pharmacy, all prescriptions must include the
physician’s special DEA number beginning with the letter X. Knowing
these important regulatory points will help pharmacists ensure that
opioid medications are being prescribed and utilized appropriately.
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NIH Pub No 11-4881. Revised October 2011.
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dispensing of narcotic drugs.
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2005. Accessed January 3, 2012.
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16. DEA announces restrictions on distribution of methadone. AAFP News Now.
Accessed January 20, 2012.
17. Code of Federal Regulations Title 42: Public Health. Part
8—certification of opioid treatment programs.
Accessed January 31, 2012.
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19. Data brief 81: Drug poisoning deaths in the United States,
1980–2008. CDC/NCHS, National Vital Statistics System.
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