Opioid Complications and Side Effects

Medications which bind to opioid receptors are increasingly being prescribed

for the treatment of multiple and diverse chronic painful conditions. Their use

for acute pain or terminal pain is well accepted. Their role in the long-term

treatment of chronic noncancer pain is, however, controversial for many rea-

sons. One of the primary reasons is the well-known phenomenon of psycho-

logical addiction that can occur with the use of these medications. Abuse and

diversion of these medications is a growing problem as the availability of these

medications increases and this public health issue confounds their clinical util-

ity. Also, the extent of their efficacy in the treatment of pain when utilized on a

chronic basis has not been definitively proven. Lastly, the role of opioids in the

treatment of chronic pain is also influenced by the fact that these potent an-

algesics are associated with a significant number of side effects and complica-

tions. It is these phenomena that are the focus of this review.

Common side effects of opioid administration include sedation, dizziness,

nausea, vomiting, constipation, physical dependence, tolerance, and respira-

tory depression. Physical dependence and addiction are clinical concerns that

may prevent proper prescribing and in turn inadequate pain management.

Less common side effects may include delayed gastric emptying, hyperalge-

sia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus.

The most common side effects of opioid usage are constipation (which has a

very high incidence) and nausea. These 2 side effects can be difficult to man-

age and frequently tolerance to them does not develop; this is especially true

for constipation. They may be severe enough to require opioid discontinuation,

and contribute to under-dosing and inadequate analgesia. Several clinical tri-

als are underway to identify adjunct therapies that may mitigate these side ef-

fects. Switching opioids and/or routes of administration may also provide bene-

fits for patients. Proper patient screening, education, and preemptive treatment

of potential side effects may aid in maximizing effectiveness while reducing the

severity of side effects and adverse events. Opioids can be considered broad

spectrum analgesic agents, affecting a wide number of organ systems and in-

fluencing a large number of body functions.

Key words: Opioids, morphine, methadone, fentsnyl, oxycodone, hydroco-

done, xymorphone, codeine, adverse events, narcotics, side effects, constipa-

tion, sedation, hearing loss, tolerance, addiction, hyperalgesia

Pain Physician 2008; 11:S105-S120

Opioid Complications and Side Effects

From:

1,8

Millennium Pain Center, Bloomington, IL;

University of Florida, Gainesville, FL, Malcom Randall

VA Medical Center;

Vanderbilt University School of

Medicine, Nashville, TN;

Dayton Pain Med, Kettering,

OH;

Pain Control Associates, Munster, IN;

University

of Wisconsin School of Medicine and Public Health,

Madison, WI;

.Pain Specialists of Greater Chicago,

Burr Ridge, IL; and

Millennium Pain Center=,

bloomingtn IL, Illinois State University, Normal, IL;

Dr. Benyamin is President, Millennium Pain Center,

Clinical Associate Professor, Department of Surgery,

College of Medicine, University of Illinois,

Urbana-Champaign, IL.

Dr. Trescot is Director of the Pain Fellowship Program

at the University of Florida and the Malcolm Randall

VA Medical Center, Gainesville, FL.

Dr. Datta is Director, Vanderbilt University

Interventional Pain Program, Associate Professor,

Dept. of Anesthesiology, Vanderbilt University

Medical Center, Nashville, TN.

Dr. Buenaventura is Medical Director, Dayton Pain

Med, and Clinical Associate Professor, Department of

Surgery, Wright State University School of Medicine,

Dayton, OH.

Dr. Adlaka is the Medical Director of Pain Control

Associates Munster, IN.

Dr. Sehgal is the Director of the Interventional Pain

Program at the University of Wisconsin School of

Medicine and Public Health and Associate Professor

Rehabilitation Medicine, Madison, WI.

Dr. Glaser is Director of the Pain Specialists of

Greater Chicago, Burr Ridge, IL.

Dr. Vallejo is Director of Research, Staff Pain

Medicine, Millennium Pain Center, Bloomington,

IL; and Adjunct Professor of Biology, Illinois State

University, Normal, IL.

Address correspondence:

Ramsin Benyamin, MD

Millennium Pain Center

1015 S. Mercer Ave.

Bloomington, IL 61701

E-mail: benyamin@millenniumpaincenter.com

Funding: Internal funding was provided by American

Society of Interventional Pain Physicians limited to

travel and lodging expenses of the authors.

Conflict of Interest: None

Free full manuscript:

Ramsin Benyamin, MD

, Andrea M. Trescot, MD

, Sukdeb Datta, MD

Ricardo Buenaventura, MD

, Rajive Adlaka, MD

, Nalini Sehgal, MD

Scott E. Glaser, MD

, and Ricardo Vallejo, MD

www.painphysicianjournal.com

Pain Physician 2008: Opioid Special Issue: 11:S105-S120 • ISSN 1533-3159

Pain Physician 2008: Opioid Special Issue: 11:S105-S120

S106 www.painphysicianjournal.com

recent efforts to address the lack of recognition and

under-treatment of chronic pain by the medical pro-

fessionals. These efforts include the regulatory require-

ment of hospitals to evaluate and address “pain,” edu-

cation by advocacy pain organizations, and aggressive

marketing by prescription opioid manufacturers to

physicians of all specialties. The confluence of these

efforts has contributed to a recent dramatic increase

in opioid prescribing.

Although the following clinical statement may be

intuitive to most physicians, its importance cannot be

overstated when utilizing opioids for the treatment of

chronic noncancer pain. Opioids should be prescribed

at the lowest dose possible to provide adequate anal-

gesia for improvement in the quality of the patient’s

life and for improvement in function. Complete pain

relief may occur but this is uncommon and cannot be

considered a treatment goal. The patient must be edu-

cated regarding these goals and continually reminded

during the course of treatment. Opioids should not be

used in isolation to treat pain and the goals of treat-

ment will commonly require additional medications

such as anticonvulsants, antidepressants, NSAIDs, and

other adjuvant treatments as well as nonpharmaco-

logic strategies. While advocacy for appropriate opi-

oid usage in chronic pain continues, it is well known

that prolonged use of opioids may result in adverse

consequences, including tolerance, hyperalgesia, hor-

monal effects, and immunosuppression.

OpiOid TOlerance and physical

ependence

Tolerance, a loss of analgesic potency, is one of

the common complications of opioid treatment, lead-

ing to ever-increasing dose requirements and decreas-

ing effectiveness over time. Physical dependence is the

development of an altered physiological state that is

revealed by an opioid withdrawal syndrome involv-

ing autonomic and somatic hyperactivity. There are 2

types of tolerance: innate (which is genetically deter-

mined and would be present from the initial dose of

the opioid) and acquired (pharmacokinetic, pharma-

codynamic, and learned) (29). Pharmacokinetic toler-

ance results from changes in the metabolism of a drug

after repeated administration, such as the induction

of an enzyme by the administration of the drug itself

(as seen with initiation of methadone treatment).

Pharmacodynamic tolerance is represented by the

classic decreased effectiveness of an opioid over time,

related to up-regulation of receptors. Learned toler-

pioids have been used for thousands of

years for the treatment of acute and

chronic pain. Around 3400 B.C., the

opium poppy was cultivated in lower Mesopotamia

by Sumerians who referred to it as Hul Gil, the “joy

plant.” The Sumerians passed along the plant and

its euphoric effects to the Assyrians and Babylonians

who in turn would pass their knowledge onto the

Egyptians. Ancient Egyptian papyrus records mention

opium as a treatment for pain (1), and in 1170, the

first book of western surgery described using sponges

soaked in opium held over the patient’s nose for

surgical procedures (2). Their use in America has

waxed and waned based on multiple and disparate

factors including availability, the introduction of

new methods of administration, regulatory efforts,

and physician and societal attitudes. Currently, the

prescribing of opioids has escalated dramatically for a

variety of reasons in the United States. Unfortunately,

but not unexpectedly, this has also been accompanied

by a concomitant and dramatic rise in the incidence

of diversion and abuse of these medications as well as

the incidence of complications including overdosage

and death.

Currently, statistics show that approximately 90%

of patients with chronic pain receive opioids (3-26),

and 90% of patients presenting to an interventional

pain management center are already on opioids (27).

It is estimated that the prevalence of a substance abuse

disorder is 8.1% in the general population (28) and

even higher in the population of patients with chronic

pain (20-26). These facts explain the dramatic rise in

prescription drug abuse and in complications second-

ary to controlled substances. One study showed that

16% of active pain patients were found to be abusing

their medications (21). In another study, Manchikanti

et al (22) reviewed the records of almost 5,500 pa-

tients, and found 91 deaths, of which 18 were drug

poisoning deaths. Of those, 12 were felt to be partially

or significantly due to prescription drugs.

Other side effects, such as constipation, nausea

and vomiting, respiratory depression, and sedation

often limit the dosing and effectiveness of opioids,

leading to early discontinuation, under-dosing, and

inadequate analgesia. Appropriate identification and

management of these side effects would be expected

to improve patient compliance and medication effi-

cacy and reduce complications.

For many years, the use of opioids for noncancer

pain was limited but this has changed secondary to

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Opioid Complications and Side Effects

ance, on the other hand, results in a decrease in effi-

cacy as compensatory mechanisms are incorporated or

learned. For instance, a patient in a setting where he

or she usually consumes the drug typically expects the

drug to be less effective; however, if the same person

takes the same amount of drug in a nonstandard set-

ting, he or she will likely feel a greater effect (30).

One concern when starting a patient on long-term

opioids has to be whether efficacy can be maintained

over time. Both acute and chronic administration of

opioids may produce tolerance as indicated by the

lowering analgesic effects of the same dose over time.

Since the initial studies by Light and Torrance in the

1920s, the major focus on research for tolerance has

been its relationship to physical and psychological de-

pendence (31). Since tolerance was considered to be

the driving force to support the street addicts’ abuse

of opioids, there was a notion that it would occur in a

similar way if opioids were used on a chronic basis in

patients with chronic pain. Physicians were reluctant

to use opioids and preferred to use them in a restric-

tive manner to preserve their efficacy for a situation

when they were really needed. However, there are no

studies to support this point of view. Interestingly, it

seems that tolerance develops at a different rate de-

pending on the specific opioid prescribed.

Although short-term studies have shown opioid

efficacy for 4 to 32 weeks, it is not ethically possible to

do placebo controlled randomized opioid trials, so the

only knowledge of long-term analgesia comes from

surveys, case series, open-label studies, and epidemio-

logic studies (32). When prescribing opioids, clinicians

should be aware of the lack of complete cross toler-

ance. That is, the development of tolerance to one

particular opioid doesn’t necessarily confer tolerance

to another. The clinical significance of this fact is para-

mount, as prescription of a new opioid at equianalge-

sic doses may lead to overdose.

Recent evidence suggests that spinal adaptations

leading to increased activity of sensory neuropeptides,

such as calcitonin gene-related peptide (CGRP) and

substance P, and their downstream signaling messen-

gers derived from metabolism of arachidonic acid such

as prostaglandins (PG), lipoxygenase (LOX) metabo-

lites, and endocannabinoids, play an important role in

the tolerance phenomenon (33).

In mice, NMDA receptor antagonists block the

development of tolerance to morphine, but not fen-

tanyl or a pure delta opioid receptor agonist; few

similar studies in humans have been performed. It is

also striking that patients on chronic opioids such as

methadone have dramatically decreased tolerance to

experimental pain (such as a cold pressor test) com-

pared to patients on no opioids (20 seconds compared

to 1 minute), despite additional high doses of mor-

phine (34).

In conclusion, although tolerance is a well known

physiologic phenomena, its clinical relevance is un-

known. Further studies to determine appropriate

methods to decrease its development and to deter-

mine its relevance are warranted.

OpiOid-induced immunOlOgic effecTs

The immunomodulatory effects of opioids were

initially demonstrated in the 1890s when Cantacuzene

showed cellular immune suppression and decreased

resistance to bacterial infection in guinea pigs treated

with morphine. Opioids have been implicated in the

increased incidence of infections in heroin addicts and

as a cofactor in the pathogenesis of human immuno-

deficiency virus. Interestingly, although exogenous

opioids may generate immunosuppression, their en-

dogenous counterparts (e.g., endorphins), induce im-

munoactivation. It is known that acute and chronic

opioid administration can cause inhibitory effects on

antibody and cellular immune responses, natural killer

cell activity, cytokine expression, and phagocytic activ-

ity. The immunologic effects of opioids are mediated

by central and peripheral mechanisms. The potential

mechanism by which central opioid receptors mediate

peripheral immunosuppression may involve the hy-

pothalamic-pituitary-adrenal axis and the autonomic

nervous system. Interestingly, peripheral immune cells

under the influence of cytokines, may release endoge-

nous opioids modulating analgesia and inflammatory

responses. Moreover, the same cells can express opioid

receptors, creating a bi-directional system whereby

opioids, immune cells, and cytokines dynamically in-

teract (35-37).

The role of different central opioid receptors in

the modulation of the immune response is variable

(Table 1). Activation of KOR (kappa opioid receptor)

and DOR (delta opioid receptor) may activate the cel-

lular immune response (38,39), while effects of MOR

(mu opioid receptor) may be more related to natural

killer (NK) cell activity, cytokine secretion, and macro-

phage phagocytosis. Probably related to the affinity of

different opioids to a particular receptor is the finding

that mice injected with morphine had a biphasic im-

mune response (40) with an increase in polymorpho-

Pain Physician 2008: Opioid Special Issue: 11:S105-S120

S108 www.painphysicianjournal.com

nuclear phagocytosis, followed by a marked decrease

24 hours later. Methadone, however, in an equianalge-

sic dose did not affect the tested immunoparameters.

In clinical practice, not all opioids have similar effects

on the immune system. Particular reference needs to

be made to tramadol, which enhances NK cell activity,

lymphocyte proliferation, and IL-2 release compared

to morphine, while buprenorphine, with its mu ago-

nist and kappa antagonist effects, doesn’t show any

effects on the immune response compared to mor-

phine. It is important to remark that severe pain by

itself has a significant immunosuppressive effect and

although the use of certain opioids may potentially in-

crease the risk of infection, the clinical significance of

this relationship between pain, analgesia, and opioid-

induced immunosuppression has not been clarified.

OpiOid-induced hOrmOnal changes

The effects of opioid compounds on hormonal

function is now fairly well understood and has been

termed opioid endocrinopathy (OE) (Table 2) or, in the

case of androgen hormones, opioid-induced andro-

gen deficiency (OPIAD) (41-43). The hormonal effects

of opioid usage affect both men and women and have

been documented during oral consumption (41,43-47)

as well as transdermal (4,44-48), intravenous (49-52),

and intrathecal (53,54) administration. OE has also

been documented in illicit drug users where serum

hormone levels return to normal following withdraw-

al from the drug (45,49,55,56). Various studies have

demonstrated opioid effects on a variety of hormones

including but not limited to testosterone (both total

Table 1. Central immunologic effects of opioids.

Receptor Effect

MOR Decreases NK cell activity (central)

Macrophage phagocytosis (central)

Inhibits T-cell proliferation (central)

Nitric oxide release (peripheral)

DOR Increases NK cell activity (central)

Potentiates humoral immune response (MOR

dependent)

Decreases PFC response

DOR

antagonist

At low dose inhibits DHR

KOR Pronounced suppression of humoral immunity

KOR

antagonist

Increases PFC

Suppression of humoral immune response

(MOR dependent)

PFC=plaque forming cells; DHR=delayed hypersensitivity reaction; NK=natural

killer

Table 2. Opioid-induced hormonal changes.

Hormone Opioid Effect Potential symptom linkage

Testosterone decrease decreased libido

erectile dysfunction

reduced energy

Estrogen decrease sexual dysfunction

reduced bone mineral density

osteoporosis

Cortisol decrease secondary hormonal alterations

Luetenizing

hormone

decrease secondary reduced androgen

hormone levels

amenorrhea

hypomenorrhea

Gonadotropin

releasing

hormone

decrease secondary reduced androgen

hormone levels

and free) (41,47), estrogen (estradiol, etc.) (42,45-

53), luteinizing hormone (LH) (42,53), gonadotrophin

releasing hormone (GnRH) (51,57,58), dehydroepi-

androsterone (DHEA) and dehydroepiandrosterone

sulfates (DHEAS) (43), adrenocorticotropin (ACTH) and

corticotropin-releasing hormone (CRH) (48,59), and

cortisol (48,59). The majority of work has focused on

the androgen hormones because of their linkage to

many symptomatic side effects of opioid usage.

Many men who are taking prescribed or illicit opi-

oids suffer from several side effects including sexual

dysfunction (i.e., erectile dysfunction, decreased li-

bido, etc.), depression, and decreased energy level.

These unwanted side effects have been correlated to

hypogonadism and likely hypogonadotrophic hypo-

gonadism (43,44,60,61). Testosterone levels are typi-

cally lowered 1 – 4 hours after acute administration

of opioids (45) and return to normal levels within 24

hours of stopping the opioid (62). Chronic administra-

tion of opioids for nonmalignant pain result in tonic

decreases in both total (TT) and free (FT) testosterone

levels in an apparent dose-dependent fashion (41,47).

It should be noted, however, that not all men show

decreased TT levels and several physiological (e.g.,

Basal Metabolic Index) and behavioral measures (e.g.,

smoking) may predispose individuals to hormonal side

effects of opioids (41). Also, it is not entirely clear that

reduced testosterone directly contributes to sexual

dysfunction. Through multivariate analyses Hallinan

and colleagues concluded that testosterone levels

contributed little variance in measures of sexual dys-

function (63). However, it should be noted that these

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Opioid Complications and Side Effects

data were obtained from addicts on methadone or

buprenorphine maintenance treatment and may not

entirely apply to patient populations taking opioids

for nonmalignant chronic pain. Studies examining

potential adjuvant therapies treating potential hor-

monally mediated side effects are rare. Daniell and

colleagues (44) performed an open-label trial of tes-

tosterone replacement therapy in men taking opioids

for chronic noncancer related pain. Although many

men showed improvement in indexes of sexual func-

tion, mood, and well-being, the effects were general-

ly incompletely resolved (44). Interestingly, the effects

of opioids on testosterone may be dependent on the

specific opioid utilized. Bliesener and colleagues (47)

studied the hormonal effects of opioid maintenance

and found that individuals taking buprenorphine had

significantly higher plasma testosterone levels and

showed less sexual dysfunction compared to patients

receiving methadone.

Again, it is unclear if these results can be extrapo-

lated to pain patient populations, but it underscores

the importance of a potential for medication depen-

dent hormonal side effects. Apart from circulating tes-

tosterone levels, adrenal androgens are also reduced

in men on prescribed opioids (42,45,53). These latter

findings suggest that opioids may not only affect hy-

pothamic-pituitary-gonadal function but also hypo-

thalamic-pituitary-adrenal function as well.

Women also experience similar hormonally linked

side effects of opioids including depression, dysmen-

orrhea, sexual dysfunction, and, potentially, reduced

bone mineral density. Several studies have demon-

strated reduced estrogen levels in women on metha-

done maintenance (42).

Reduced LH is also observed and appears to be more

pronounced in postmenopausal women. Interestingly,

testosterone levels also appear to be reduced in women

taking prescribed opioids and may be related to body

mass index and estrogen replacement therapy (64). The

direct consequences of reduced LH and progesterone

levels on dysmenorrhea are currently unclear.

The reductions in estrogen may have implications

for osteoporosis and fractures in the older population.

Ensrud and colleagues (64) found that, in a cohort of

8,127 older women, patients that were taking opioids

had a greater risk for any nonspinal fracture. Some have

suggested that, in part, this relative increase in risk of

fracture may be due to an androgen-based reduction in

bone density (65-67). While this is a plausible hypothesis,

there is a lack of causal data connecting the hormonal ef-

fects of opioids to reduced bone mineral density. More-

over, while estrogen replacement therapy may be use-

ful in some women to restore menses or maintain bone

mineral density in younger women, there have been no

controlled studies weighing the benefits of such therapy

against the well publicized risks associated with estro-

gen replacement therapy.

OpiOid-induced hyperalgesia

Hyperalgesia (also referred to as hyperalgia) is a

relatively new recognized adverse effect, and is gen-

erally defined as an increased pain sensitivity (68).

This sensitization presents as increasing pain despite

increasing doses of opioids (69). Long-term use and

high doses of opioids may be associated with the

development of hyperalgesia, which may be related

to opioid metabolites, such as morphine 3-glucero-

nide (M3G). Opioid-induced cell apoptosis may also

be associated with hyperalgesia. The loss of GABA

neurons to apoptosis may result in changes in spinal

neuronal circuits (70). NMDA receptor agonism also

has a major role in the development of hyperalge-

sia, as does glycine, an inhibitory neurotransmitter

that mediates the postsynaptic inhibition of spinal

neurons (71). At least in mice, the use of an L-type

calcium channel blocker (amlodipine) prevented the

hyperalgesia and tolerance of chronic morphine ad-

ministration (72). This is consistent with the concept

that morphine-induced abnormal pain and antino-

ciceptive tolerance may be mediated by enhanced

release of excitatory neurotransmitters (73). There

are limited treatment options for the hyperalgesia

and tolerance; in rats, ketamine (a NMDA antago-

nist) prevented fentanyl-induced hyperalgesia (74).

Recent studies in opioid addicts have helped to con-

firm the clinical impression that chronic opioid use

results in an abnormal pain perception, consistent

with hyperalgesia (75).

OpiOid-induced sedaTiOn

The sedating effects of opioids in opioid naïve pa-

tients are fairly well known (76). Opioid-induced seda-

tion and drowsiness are thought to be caused by the

anticholinergic activity of opioids. Although tolerance

to these side effects often develops, dose initiation

and rapid dose escalation may result in sedation and

consequently lead to noncompliance and/or reduced

quality of life. The suggested treatments are opioid

dose reduction, opioid rotation, and use of psychoso-

matic stimulants.

Pain Physician 2008: Opioid Special Issue: 11:S105-S120

S110 www.painphysicianjournal.com

Psychostimulants may improve psychomotor

performance scores and subjective drowsiness (77).

Methylphenidate is the most common medication

investigated to treat opioid-induced sedation. In a

double-blind randomized study of cancer patients re-

ceiving continuous subcutaneous opioids, a daily dose

of 10 mg methylphenidate significantly improved the

mean baseline drowsiness scores by 35% compared

with 8% in the placebo group (78). In another double-

blind, randomized study in cancer patients, 15 mg of

daily methylphenidate use led to a 61% improvement

in drowsiness score, with only 25% improvement in

the placebo group; at the same time, there was an

associated decreased pain and decreased number of

opioid doses (79). A 15 mg daily dose of methylpheni-

date was studied in a double-blind randomized fash-

ion in 32 cancer patients maintained on a steady dose

of oral opioids (80). The treatment group had a 61%

improvement in drowsiness score, which was signifi-

cantly greater than 25% improvement in the placebo

group. Methylphenidate was also associated with de-

creased pain and rescue opioid doses. Multiple uncon-

trolled studies have also demonstrated positive results

with methylphenidate. Although other options like

dextroamphetamine, donepezil, modafinil, and caf-

feine are also available, methylphenidate is the most

widely studied agent, and in absence of side effects

and abuse potential it should be considered as first

line therapy (81).

OpiOid-induced sleep disTurbances

Sleep disturbance is common in cancer patients

(82). It is usually attributed to insomnia or pain, but

there is little evidence to support this. Arousal from

sleep or disturbed sleep from pain has been reported

but there is some evidence that patients in pain do

not suffer from disturbed sleep more than those not

in pain. In addition, no correlation has been found

between pain severity and sleep disturbance. The ef-

fect of opioids on sleep in palliative care patients has

not been well studied. Opioids are generally believed

to enhance sleep but again, there is little evidence to

support this belief.

Opioids increase the number of shifts in sleep-

waking states (83), and decrease total sleep time,

sleep efficiency (84),

delta sleep, and REM sleep (85).

However, in these studies, it is difficult to differentiate

the effects of the opioid medication from the effects

of the underlying disorders (e.g., cancer, addiction/de-

pendence, postoperative pain). A study of 7 healthy

volunteers treated with IV morphine showed reduc-

tions in slow wave sleep and a mild decrease in REM,

but no increase in awakenings or arousals (86). A ran-

domized, double-blind study (87) involving 42 healthy

volunteers given 5 mg methadone or 15 mg sustained

release morphine, showed that both opioids increased

the percentage of time spent in light sleep and sub-

stantially decreased (30% to 50%) the percentage of

time in deep sleep (stages 3 and 4). No drug effects

were seen on sleep efficiency, total sleep time, wake

after sleep onset, or subjective measures of mood

or fatigue. Both cortical arousal and the sleep-wake

cycles are regulated by converging inputs from the

brainstem and pontinecholinergic projections (88).

Sleep and waking is regulated by many neurotrans-

mitters, including noradrenaline, serotonin, acetyl-

choline, dopamine, histamine, gamma-aminobutyric

acid (GABA), the pituitary hormones, and the neuro-

hormone melatonin. Any drugs that alter the balance

of these neurotransmitters, as opioids do, can poten-

tially affect sleep. Although the exact mechanism by

which opioids disrupt sleep is unclear, morphine has

been shown to reduce REM sleep perhaps in part by

modulating GABAergic signaling via inhibition of ace-

tylcholine release in the medial pontine reticular for-

mation. The resultant disruption of sleep architecture

affects the states of arousal during wakefulness (89).

In animals, REM suppression is associated with mu, but

not kappa or delta opioid receptor agonists.

psychOmOTOr perfOrmance in OpiOid

herapy

The negative effects of opioids on psychomotor/

driving performance in opioid naïve patients remains

controversial in the minds of clinicians — multiple stud-

ies support the notion that for many patients it is rea-

sonable to drive on a stable dose of opioids (76,90-92).

When opioids are initially added to the management

of pain, patients’ abilities to operate heavy equipment

may be diminished and so they should not be allowed

to drive automobiles; however, once a stable opioid an-

algesic regimen is reached, patients with no significant

cognitive/psychomotor impairments should be allowed

to drive — as they would be allowed to drive with any

medication which can potentially cause central nervous

system depression (e.g., antidepressants). In contrast,

others believe that patients on stable doses of opioid

medications should be allowed to drive vehicles (93).

Direct evidence provided in a subset of patients with

chronic pain on a stable opioid analgesic regimen (76)

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Opioid Complications and Side Effects

showed that these patients were capable of operat-

ing automobiles safely during daytime, in normal cli-

mate weather. A structured, evidence-based review

by Fishbain et al (94) suggested that in opioid-depen-

dent/tolerant patients on stable doses of opioids, no

impairment of psychomotor abilities are observed even

immediately after a dose of opioid.

OpiOid-induced cOnsTipaTiOn

Constipation is a common problem, occurring

in 40% to 95% of patients treated with opioids

and can occur even with a single dose of morphine

(95). Although often dismissed as a trivial side ef-

fect, the long-term consequences of constipation

can result in significant morbidity and mortality,

with an adverse effect on patient quality of life. Se-

vere constipation can force patients to reduce the

dose of the opioid, resulting in decreased analgesia.

Chronic constipation can result in hemorrhoid for-

mation, rectal pain and burning, bowel obstruction,

and potential bowel rupture and death. Opioids

activate mu receptors in the gastrointestinal tract

responsible for gut motility (84) from a vascular dis-

tribution as well as local application to the gut (96).

Reported rates of constipation with spinal adminis-

tration of opioids vary, but in general it is thought

that spinal opioid receptors do not affect intestinal

motility and transit in humans (61,97). It is unclear

whether opioid-induced constipation in humans is

predominantly centrally mediated or peripherally

mediated. Morphine may act within the CNS to alter

autonomic outflow to the gut (98). Peripherally it

affects intestinal motility by a direct stimulation of

opioid receptors in the enteric nervous system (99).

Loperamide, an opioid receptor agonist with limited

ability to cross the blood brain barrier, is used clini-

cally to treat diarrhea, suggesting that opioids have

a more direct local constipating effect.

Unlike many of the other side effects of opioids

(respiratory depression, nausea, sedation), consti-

pation is unlikely to improve over time, and there-

fore must be anticipated, monitored, and addressed

throughout the opioid treatment course (100) (Table

3). It is suggested that tolerance may be linked to

certain subtypes of mu receptors that mediate vari-

ous pharmacological actions (99). Tolerance develops

more readily to mu-1-dependent actions than to non-

mu-1-dependent actions. Another hypothesis suggests

that development of tolerance requires P-glycopro-

tein up-regulation. Morphine induces P-glycoprotein

up-regulation in the brain, but it does not up-regulate

intestinal P-glycoprotein (101).

Assessment of constipation can be difficult; a

questionnaire (Patient Assessment of Constipation)

that measures symptom severity (PAC-SYM) and qual-

ity of life (PAC-QOL) can be used (102). The question-

naire was validated in chronic low back pain patients

and found to be a reliable, valid, and responsive mea-

sure of the presence and severity of opioid-induced

constipation symptoms.

There is a need for effective treatment of opiate-

induced constipation. It is partially attenuated by us-

ing different types of opioid compounds or routes of

administration or combining opioids with other medi-

cations. However, refractory constipation may still de-

velop and opioid antagonists may play an important

therapeutic role in this respect. Antagonizing the gas-

trointestinal mu receptors is the basis for many current

investigational medications to treat opioid-induced

constipation.

A novel approach to management of opioid-

induced constipation involves blocking peripheral

opioid receptors in the gut with opioid receptor

antagonists with prokinetic activity. Two recently

developed mureceptor antagonists, methylnaltrex-

one and alvimopan, are currently under review

(103). Methylnaltrexone is a quaternary derivative

of naltrexone with strong mureceptor affinity but

no intrinsic agonist activity; it blocks the peripheral

actions of opioids while sparing central analgesic

effects and reverses the gut-slowing action of mor-

phine. It is currently under late-stage clinical inves-

tigation for the treatment of opioid-induced consti-

pation in patients with advanced illness. Alvimopan,

a selective, competitive mureceptor antagonist with

limited oral bioavailability, has been used to reduce

the length of postoperative ileus. A systematic re-

view of available data shows proof of concept but

does not conclusively demonstrate the efficacy of

peripherally acting muopioid antagonists in manag-

ing opiate-related constipation (103).

OpiOid-induced bladder dysfuncTiOn

The risk of opioid-induced bladder dysfunction

(i.e., difficulty voiding or frank urinary retention) is a

significant problem in postoperative patients, but the

incidence has been difficult to estimate because many

other factors can play a role. Two studies reported uri-

nary retention in 3.8% and 18.1% of patients receiving

opioids in the postoperative period (104,105). Urinary

Pain Physician 2008: Opioid Special Issue: 11:S105-S120

S112 www.painphysicianjournal.com

Table 3. Medications for treatment of chronic constipation.

Agent Formula/strength Adult dosage Side effects/complications

Bulk laxatives

Methylcellulose

(Citrucel)

Powder: 2 g (mix with 8 oz liquid)

Tablets: 500 mg (take with 8 oz liquid)

One to 3 times

daily

2 tablets up to 6

times daily

Bulk mass may predispose inactive patients to

obstruction. Most common side effect is increased

intestinal gas.

Polycarbophil

(Fibercon)

Tablets: 625 mg 2 tablets 1 to 4

times daily

Bulk mass may predispose inactive patients to

obstruction. Most common side effect is increased

intestinal gas.

Psyllium (Metamucil) Powder: 3.4 g (mix with 8 oz liquid) 1 to 4 times daily Bulk mass may predispose inactive patients to

obstruction. Most common side effect is increased

intestinal gas.

Stool softeners

Docusate calcium

(Surfak)

Capsules: 240 mg Once daily Ineffective unless adequate fluid intake. Ineffective as

sole agent in patients with decreased bowel motility.

Contra-indicated with mineral oil laxatives.

Docusate sodium

(Colace)

Capsules: 50 or 100 mg

Liquid: 150 mg per 15 mL

Syrup: 60 mg per 15 mL

50 to 300 mg Ineffective unless adequate fluid intake. Ineffective as

sole agent in patients with decreased bowel motility.

Contraindicated with mineral oil laxatives.

Osmotic laxatives

Lactulose Liquid: 10 g per 15 mL 15 to 60 mL daily Possible side effects include flatulence, abdominal

cramps, diarrhea, or nausea or vomiting. Use with

caution in diabetics.

Magnesium citrate Liquid: 296 mL per bottle 0.5 to 1 bottle per

day

Possible side effects include diarrhea and electrolyte

imbalances. Rarely considered first-line therapy

due to their undesirably strong and quick laxative

activity. Use with caution in patients with decreased

renal function. Excess magnesium can cause CNS

depression, muscle weakness, and EKG changes.

Magnesium hydroxide

(Milk of Magnesia)

Liquid: 400 mg per 5 mL 30 to 60 mL once

daily

Possible side effects include diarrhea and electrolyte

imbalances. Rarely considered first-line therapy

due to their undesirably strong and quick laxative

activity. Use with caution in patients with decreased

renal function. Excess magnesium can cause CNS

depression, muscle weakness, and EKG changes.

Polyethylene glycol

3350 (Miralax)

Powder: 17 g (mix with 8 oz liquid) Once daily Side effects include abdominal pain, bloating,

cramping, and increased intestinal gas. More severe

side effects include diarrhea and hives.

Sodium biphosphate

(Phospho-Soda)

Liquid: 45 mL, 90 mL (mix with 4 oz

water, then follow with 8 oz water)

20 to 45 mL daily Use with caution in patients on sodium restricted

diets. Use with caution in patients with decreased

renal function.

Sorbitol Liquid: 480 mL 30 to 150 mL daily Side effects may include nausea, gas, diarrhea,

stomach cramps, or anal irritation.

Stimulant laxatives

Bisacodyl (Dulcolax) Tablets: 5 mg 5 to 15 mg daily Side effects may include stomach ache, cramping,

weakness, sweating, irritation of the rectal area,

diarrhea, or dizziness. Do not use in presence of

nausea, vomiting, or other symptoms of bowel

obstruction.

www.painphysicianjournal.com S113

Opioid Complications and Side Effects

retention is much more likely to occur after epidural

injection of morphine rather than intravenous or in-

tramuscular injection (106). The mechanism of urinary

retention is still not completely understood. Opioids

are well known to decrease detrusor tone and the

force of contraction, decrease the sensation of fullness

and urge to void, and inhibit the voiding reflex. They

probably do not increase sphincter tone (107). These

effects are naloxone reversible. Animal and human

studies suggest a significant centrally mediated effect

on the brain and spinal cord, although peripheral ef-

fects at the bladder may also play a role. Rosow and

colleagues (108) demonstrated that opioid-induced

changes in bladder function are due, in part, to a pe-

ripheral opioid effect and can be reversed by methyln-

altrexone, a peripheral opioid antagonist indicating

that peripheral mechanisms may play a role.

cardiac effecTs Of OpiOids

The cardiac side effects of opioids are not very

common. Morphine has been associated with hista-

mine release and consequent vasodilation and hypo-

tension (109). This adverse effect is partially blocked by

H1 antagonism but completely reversed by naloxone.

Parasympathetic stimulation may also contribute to

bradycardia. Recently, a syndrome of QT prolongation

and torsade des pointes (Tdp) has drawn some atten-

tion partially due to an increase in use of methadone

for treatment of chronic pain (110,111). Mortality rate

due to Tdp could be as much as 17% (112) and there-

fore it is prudent to monitor the EKG for presence of

QT prolongation in patients receiving methadone.

Methadone can block the human ether-a-go-go-

related-gene (hERG) channel causing QT prolongation

and torsades de pointes ventricular tachycardia (113-

Agent Formula/strength Adult dosage Side effects/complications

Cascara sagrada Liquid: 120 mL

Tablets: 325 mg

5 mL once daily

1 tablet daily

Side effects may include strong cramping in the

abdomen, electrolyte imbalance (loss of potassium),

loss of body fluids, and dark pigmentation in the

colon, called melanosis coli. Long-term use has been

linked to the development of colorectal growths

(adenomas) and cancer. Interaction may occur with

cardiac glycosides, such as digitalis. Do not use in

presence of nausea, vomiting, or other symptoms of

bowel obstruction.

Castor oil Liquid: 60 mL 15 to 60 mL once

daily

Side effects can include abdominal pain or cramping,

colic, nausea, vomiting, and diarrhea. Long-term

use of castor oil can lead to fluid and electrolyte loss.

Do not use in presence of nausea, vomiting, or other

symptoms of bowel obstruction. Contraindicated in

pregnancy or during breastfeeding.

Senna (Senokot) Tablets: 8.6 mg 2 or 4 tablets once

or twice daily

Side effects may include strong cramping and

abdominal pain, electrolyte imbalance (loss of

potassium), loss of body fluids, nausea, rash, swelling

of the fingertips, weight loss, and dark pigmentation

in the colon, called melanosis coli. Long-term use has

been linked to the development of colorectal growths

(adenomas) and cancer. May interact with calcium

channel blockers and Indocin. It has been linked to

liver toxicity.

Prokinetic Agents

Tegaserod (Zelnorm) Tablets: 2 mg, 6 mg 2 times daily‡ In March 2007, the FDA asked Novartis to stop sales

of Zelnorm in the U.S. effective immediately. The

FDA’s action was the result of a new analysis of 29

clinical studies of Zelnorm that showed an increased

risk of heart attack, stroke, and angina (chest pain)

in patients who took Zelnorm. Side effects include

headache, abdominal pain, and diarrhea. Other

side effects include rectal bleeding, bloody diarrhea,

or new or worsening abdominal pain that may be

symptoms of intestinal ischemia.

Table 3. Continued.

Pain Physician 2008: Opioid Special Issue: 11:S105-S120

S114 www.painphysicianjournal.com

115). The incidence of tachycardia-corrected QT pro-

longation (QTc) of greater than 500 milliseconds was

found to be 16% among heroin addicts treated with

methadone, and TdP occurred in 3.6% of that same

group (116). The absolute QTc value of 500 ms has been

known as a definite risk factor to develop Tdp. But,

some have suggested that a QT prolongation of more

than 30 ms from the baseline should be considered clini-

cally significant, and more than 60 ms prolongation be-

yond baseline is a risk factor to develop Tdp (117,118).

The QTc prolongation by methadone has been attrib-

uted to its (R)-enantiomer which has 50 times more an-

algesic potency than its (S)-enantiomer (119). Clinically

significant QTc prolongation has been mostly observed

in patients taking total daily doses of more than 40 mg

methadone (120). But in a recent retrospective review,

lower daily doses of 30 mg methadone were found

to cause QTc prolongation, and Tdp was observed in

patients receiving daily doses of 40–200 mg metha-

done. Significant correlation was observed between

QTc prolongation and patients receiving methadone

and CYP3A4 inhibitors like fluoxetine, clarithromycin,

fluconazole, and valproate (116). The same report also

identified hypokalemia and diminished liver function

as other risk factors for developing QTc prolongation.

Previously in separate reports, other medications like

cocaine, tricyclic antidepressants, quinine, haloperidol,

droperidol, chlorpromazine, and erythromycin had

been implicated to cause QTc prolongation (Table 4).

An updated list of medications causing Tdp-VT can be

found at www.qtdrugs.org.

The serious consequence of QTc prolongation has

prompted some to recommend repeated surface EKGs

during the course of treatment with methadone, es-

pecially when raising the dose and adding other medi-

cations like CYP3A4 inhibitors and also when hypoka-

lemia and diminished liver function are present (121).

adverse effecTs Of specific OpiOids

This section explores both common and uncom-

mon specific complications of the administration of

several medications including codeine, hydrocodone,

hydromorphone, oxycodone, oxymorphone, mor-

phine, and fentanyl.

Codeine is commonly used in the postpartum pe-

riod for pain associated with episiotomy and cesarean

section. As most mothers initiate breastfeeding, the

safety of codeine and its pharmacologically active me-

tabolite, morphine, amongst breastfed infants is of

primary concern. The American Academy of Pediatrics

lists codeine as compatible with breastfeeding. How-

ever, Koren et al (83) published a case of a full-term,

breastfed infant who died in a manner consistent with

morphine overdose. An explanation proposed was

that if the mother is an ultrarapid metabolizer of cyto-

chrome P450 2D6, she produces much more morphine

when taking codeine than most people do. Options to

reduce the risk include discontinuing codeine after 2

– 3 days of use and being aware of symptoms of po-

tential opioid toxicity in both mothers and newborns.

Hydrocodone/acetaminophen is one of the most

commonly prescribed medications for both acute and

chronic pain relief in the United States, and is effective

as both an antitussive and opioid analgesic. Common

adverse reactions to this medication combination in-

clude dizziness, nausea, vomiting, drowsiness, and eu-

phoria. Respiratory depression and mood disturbance

are rare. As with all opioids, hydrocodone may lead to

physical and psychological dependence. Hearing loss is

an infrequently recognized side effect of hydrocodone

use, with only a few case reports to date. Friedman et

al (122) described 12 patients with profound hearing

loss attributed to hydrocodone (4 were initially unilat-

eral); none noted relief after high dose steroids, and

7 of the 8 who underwent cochlear implantation had

good early response. Ho et al (123) described the clini-

cal characteristics of 5 patients who presented with

progressive sensorineural hearing loss, suspected to be

due to chronic hydrocodone/acetaminophen use. The

admitted hydrocodone dose ranged from 10 to 300 mg

per day. None responded to high dose steroids, and all

responded to cochlear implant. The authors felt that

genetic polymorphisms of the drug metabolizing en-

zymes CYP2D6 or CYP3D4 or associated comorbidities

such as hepatitis C may predispose certain individuals

to adverse reactions to the drug. It is unclear whether

the hearing loss is due to the hydrocodone or the as-

sociated acetaminophen.

Table 4. Factors correlated with QT prolongation in methadone

use.

• CYP3A4 inhibitors (e.g. fluoxetine, clarithromycin, fluconazole

and valproate)

• Hypokalemia

• Diminished liver function

• Cocaine

• Tricyclic antidepressants

• Haloperidol

• Droperidol

www.painphysicianjournal.com S115

Opioid Complications and Side Effects

OROS hydromorphone is a controlled-release for-

mulation that uses an active osmotic system to deliver

consistent levels of hydromorphone over 24 hours and

achieve rapid steady state concentrations. Wallace at el

(124) investigated the safety and efficacy of once-daily

OROS hydromorphone in patients with moderate-to-

severe chronic low back pain. The study involved 209

patients randomized to receive treatment in 15 North

American study centers. The most common side ef-

fects included constipation (20.9%), nausea (19.8%),

vomiting (9.7%), headache (14.0%), and somnolence

(14.0%). Long-acting opioids usually cause similar ad-

verse event profiles to short-acting agents, with the

most frequent effects on the gastrointestinal and ner-

vous systems.

Oxymorphone is an opioid specific for the mu re-

ceptor and is approved to treat both acute and chronic

pain. Chamberlin et al (125) described the pharmacol-

ogy, safety, efficacy, and usage of oral oxymorphone

for pain management. Unlike oxycodone, it does not

bind the kappa opioid receptor. This medication un-

dergoes extensive hepatic metabolism and it is con-

traindicated in patients with moderate to severe liver

impairment. However, there is no report of significant

CYP3A4, 2C9, or 2D6 drug interactions. The absence of

CYP2D6 metabolism limits its potential to cause some

of the more common drug interactions via the CYP450

system. The elderly can experience a 40% increase in

plasma concentrations while renally impaired patients

may have a 57 – 65% increase in bioavailability. Food

can also increase the rate of absorption by as much

as 50%, necessitating dosing either 1 hour before or

2 hours after a meal. Primary adverse side effects in-

clude nausea, vomiting, pruritus, pyrexia, and consti-

pation. Notably, the manufacturer lists nausea and py-

rexia as the most common (defined as >10%). Caution

is also warranted with using oxymorphone with other

CNS depressants including opioids, general anesthet-

ics, antidepressants, phenothiazines, sedatives, and

hypnotics. The manufacturer also warns of confusion,

disorientation, respiratory depression, apnea, and sei-

zures when oxymorphone is given with cimetidine.

However, no cause and effect relationship is known or

given for this warning. Mixed agonist/antagonist an-

algesics (e.g., butorphanol, buprenorphine) can also

reduce the medication’s efficacy and precipitate with-

drawal symptoms in patients who take oxymorphone.

Respiratory depression is also a concern and the medi-

cation is prescribed with caution in patients with hy-

poxia, hypercapnia, or decreased respiratory reserve.

Further, this medication may aggravate seizures in pa-

tients with seizure disorders, as all opioids can poten-

tially lower the seizure threshold. Additionally, since

opioids may cause sphincter of Oddi spasm, plasma

amylase and lipase levels may unexpectedly increase.

Caution is warranted in patients with biliary tract dis-

ease such as acute pancreatitis or cholelithiasis.

Oxycodone CR is a long-acting opioid used for the

treatment of noncancer pain. Portenoy et al (126) per-

formed an open-label, uncontrolled, prospective lon-

gitudinal investigation of outcomes associated with

use of Oxycodone CR. The study provides evidence that

the greatest need for dose titration occurs during the

first 3 months for most patients, after which further

dose escalation is minimal. During the 3 year study,

the most common adverse events included constipa-

tion (15%) and nausea (12%). Other adverse events

included somnolence (8%), vomiting (7%), and de-

pression (2%). After the first 3 months, the incidence

of all the common adverse events except depression

declined substantially. The most serious adverse events

included chest pain and accidental injury. All patients

with chest pain had cardiac risk factors at the time of

study entry and the accidental injuries reported were

mostly fractures.

Morphine is used for the treatment of noncan-

cer pain. Osteoarthritis is often treated with opioids

as NSAIDS may cause gastrointestinal injury as well as

renal compromise. The efficacy and safety of several

branded sustained release morphine medications has

been studied in randomized trials to be comparable to

generic sustained release morphine (127). Constipation

is one of the primary reasons for adverse event related

patient withdrawal in this study.

Fentanyl is also used for the treatment of chronic

low back pain. The delivery systems include transder-

mal, buccal tablet, and oral transmucosal prepara-

tions. Allan et al (128) studied the use of transdermal

fentanyl (TDF) in strong opioid naïve patients with

chronic low back pain in an open, randomized, par-

allel group multicenter study. This study looked at

the efficacy and safety of TDF and sustained release

morphine (SRM) in strong opioid naïve patients with

chronic low back pain. Data from 680 patients studied

over 13 months showed similar pain relief with both

medications but TDF caused significantly less constipa-

tion. Another study by Portenoy et al (129) studied the

fentanyl buccal tablet (FBT) for relief of breakthrough

pain in opioid-treated patients with chronic low back

pain with a randomized, placebo-controlled study.

Pain Physician 2008: Opioid Special Issue: 11:S105-S120

S116 www.painphysicianjournal.com

FBT is a new formulation of fentanyl that enhances

transbuccal drug delivery via an effervescent reaction.

Currently it is FDA approved for cancer related break-

through pain. Adverse events were reported in 65%

of patients including nausea (19%), dizziness (13%),

somnolence (9%), dysgeusia (8%), vomiting (6%),

and dry mouth (5%). Two patients experienced seri-

ous adverse events during the study including diabetic

gastroparesis and accidental overdose resulting in

loss of consciousness. This patient took 4 of the 600

mcg tablets without explanation. He fully recovered

after resuscitation with oxygen and admission to the

hospital. This is an untoward opioid-related effect,

which may make this medication seem less attractive

for breakthrough back pain. The study did show FBT is

generally well tolerated at doses of 100 – 800 mcg and

provides evidence that a rapid-onset opioid is useful

for pain not associated with cancer.

discussiOn

Adverse events related to the opioids discussed

above appear similar except for a few exceptions. In

general, they appear to fall into 2 broad categories:

nonlife-threatening and life-threatening. Hydroco-

done may cause sensorineural hearing loss due to pos-

sible genetic polymorphisms. Constipation and nausea

are the most common adverse effects and also lead

to dropouts in controlled trials. Both constipation and

nausea occurred more often with opioid therapy com-

pared to treatment with tricyclic antidepressants in

the only study that compared these 2 treatments with

placebo in postherpetic neuralgia (130). Dellemijn et

al (131) reported high incidence of sweating, anorex-

ia, and clouded vision. Their study also assessed the se-

verity of adverse effects and found that the mean in-

tensity of adverse effects, particularly that of sedation,

decreased gradually over 2 – 3 months. Tolerance may

not develop to the constipating effects of opioids, and

so constipation should be treated early and effective-

ly. Two RCTs on oral opioids (132,133) reported with-

drawal symptoms that occurred in 1 – 2% of patients.

After the treatment period, drug craving was reported

by 8.7% of patients on morphine compared with 4.3%

on placebo (134). The Cochrane review of opioids for

neuropathic pain (135) reported a majority of adverse

events and withdrawals from 8 intermediate term

placebo controlled trials (130,136-141). Analysis of 4

studies reviewed by the authors of the Cochrane re-

view (136,137,139,141) revealed that 23 (11%) of 212

patients withdrew because of adverse events during

opioid therapy versus 9 (4%) of 202 receiving placebo.

Another study (142) reported adverse events on a VAS,

precluding determination of the numbers of affected

participants. The most common adverse events were

nausea (33% opioid versus 9% control) and constipa-

tion (33% opioid versus 10% control), followed by

drowsiness (29% opioid versus 6% control), and vom-

iting (15% opioid versus 3% control).

With all opioids, respiratory depression and death

are the most feared complications. From 1979 to 1990,

unintentional drug poisoning death rates were on av-

erage 5.3% per year; however, from 1990 to 2002, the

rate increased to 18.1% per year. In that same time

period, the number of opioid analgesic poisonings on

death certificates increased 91.2%, while heroin deaths

increased only 12.4% and cocaine deaths 22.8%. The

increase in deaths generally matched the increase in

sales for each type of opioid.

Drug deaths from opioids are a serious and in-

creasing issue. Effective patient compliance with ap-

propriate medical treatment programs are needed to

prevent rare but life-threatening adverse events.

cOnclusiOn

There is evidence that opioid medications can be

effective in treating a variety of chronic pain condi-

tions but, like most pharmaceutical based therapies,

their use can be potentially accompanied by side ef-

fects and complications. Despite the rise in serious

adverse events involving the use of opioids, includ-

ing death, these medications continue to be widely

prescribed in the majority of patients suffering from

chronic pain. Proper prescribing practices as well as

physician and patient education can help manage tol-

erance issues, adverse events, as well as common and

uncommon side effects.

Opioid Complications and Side Effects

www.painphysicianjournal.com S117

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