Opioid Complications and Side Effects
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Pain Physician 2008: Opioid Special Issue: 11:S105-S120 • ISSN 1533-3159
Opioid Complications and Side Effects
Ramsin Benyamin, MD1, Andrea M. Trescot, MD 2, Sukdeb Datta, MD3,
Ricardo Buenaventura, MD4, Rajive Adlaka, MD5, Nalini Sehgal, MD6,
Scott E. Glaser, MD7, and Ricardo Vallejo, MD8
From: 1,8Millennium Pain Center, Bloomington, IL;
University of Florida, Gainesville, FL, Malcom Randall
2
VA Medical Center; 3Vanderbilt University School of Medications which bind to opioid receptors are increasingly being prescribed
Medicine, Nashville, TN; 4Dayton Pain Med, Kettering, for the treatment of multiple and diverse chronic painful conditions. Their use
OH; 5Pain Control Associates, Munster, IN; 6University for acute pain or terminal pain is well accepted. Their role in the long-term
of Wisconsin School of Medicine and Public Health, treatment of chronic noncancer pain is, however, controversial for many rea-
Madison, WI; 7.Pain Specialists of Greater Chicago,
Burr Ridge, IL; and 8Millennium Pain Center=,
sons. One of the primary reasons is the well-known phenomenon of psycho-
bloomingtn IL, Illinois State University, Normal, IL; 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
Dr. Benyamin is President, Millennium Pain Center, medications increases and this public health issue confounds their clinical util-
Clinical Associate Professor, Department of Surgery, ity. Also, the extent of their efficacy in the treatment of pain when utilized on a
College of Medicine, University of Illinois, chronic basis has not been definitively proven. Lastly, the role of opioids in the
Urbana-Champaign, IL.
Dr. Trescot is Director of the Pain Fellowship Program
treatment of chronic pain is also influenced by the fact that these potent an-
at the University of Florida and the Malcolm Randall algesics are associated with a significant number of side effects and complica-
VA Medical Center, Gainesville, FL. tions. It is these phenomena that are the focus of this review.
Dr. Datta is Director, Vanderbilt University
Interventional Pain Program, Associate Professor, Common side effects of opioid administration include sedation, dizziness,
Dept. of Anesthesiology, Vanderbilt University nausea, vomiting, constipation, physical dependence, tolerance, and respira-
Medical Center, Nashville, TN.
Dr. Buenaventura is Medical Director, Dayton Pain
tory depression. Physical dependence and addiction are clinical concerns that
Med, and Clinical Associate Professor, Department of may prevent proper prescribing and in turn inadequate pain management.
Surgery, Wright State University School of Medicine, Less common side effects may include delayed gastric emptying, hyperalge-
Dayton, OH. sia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus.
Dr. Adlaka is the Medical Director of Pain Control The most common side effects of opioid usage are constipation (which has a
Associates Munster, IN. very high incidence) and nausea. These 2 side effects can be difficult to man-
Dr. Sehgal is the Director of the Interventional Pain
Program at the University of Wisconsin School of
age and frequently tolerance to them does not develop; this is especially true
Medicine and Public Health and Associate Professor for constipation. They may be severe enough to require opioid discontinuation,
Rehabilitation Medicine, Madison, WI. and contribute to under-dosing and inadequate analgesia. Several clinical tri-
Dr. Glaser is Director of the Pain Specialists of als are underway to identify adjunct therapies that may mitigate these side ef-
Greater Chicago, Burr Ridge, IL. fects. Switching opioids and/or routes of administration may also provide bene-
Dr. Vallejo is Director of Research, Staff Pain fits for patients. Proper patient screening, education, and preemptive treatment
Medicine, Millennium Pain Center, Bloomington,
IL; and Adjunct Professor of Biology, Illinois State
of potential side effects may aid in maximizing effectiveness while reducing the
University, Normal, IL. severity of side effects and adverse events. Opioids can be considered broad
spectrum analgesic agents, affecting a wide number of organ systems and in-
Address correspondence: fluencing a large number of body functions.
Ramsin Benyamin, MD
Millennium Pain Center Key words: Opioids, morphine, methadone, fentsnyl, oxycodone, hydroco-
1015 S. Mercer Ave.
Bloomington, IL 61701
done, xymorphone, codeine, adverse events, narcotics, side effects, constipa-
E-mail: benyamin@millenniumpaincenter.com tion, sedation, hearing loss, tolerance, addiction, hyperalgesia
Funding: Internal funding was provided by American Pain Physician 2008; 11:S105-S120
Society of Interventional Pain Physicians limited to
travel and lodging expenses of the authors.
Conflict of Interest: None
Free full manuscript:
www.painphysicianjournal.comPain Physician 2008: Opioid Special Issue: 11:S105-S120
O 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
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
plant.” The Sumerians passed along the plant and marketing by prescription opioid manufacturers to
its euphoric effects to the Assyrians and Babylonians physicians of all specialties. The confluence of these
who in turn would pass their knowledge onto the efforts has contributed to a recent dramatic increase
Egyptians. Ancient Egyptian papyrus records mention in opioid prescribing.
opium as a treatment for pain (1), and in 1170, the Although the following clinical statement may be
first book of western surgery described using sponges intuitive to most physicians, its importance cannot be
soaked in opium held over the patient’s nose for overstated when utilizing opioids for the treatment of
surgical procedures (2). Their use in America has chronic noncancer pain. Opioids should be prescribed
waxed and waned based on multiple and disparate at the lowest dose possible to provide adequate anal-
factors including availability, the introduction of gesia for improvement in the quality of the patient’s
new methods of administration, regulatory efforts, life and for improvement in function. Complete pain
and physician and societal attitudes. Currently, the relief may occur but this is uncommon and cannot be
prescribing of opioids has escalated dramatically for a considered a treatment goal. The patient must be edu-
variety of reasons in the United States. Unfortunately, cated regarding these goals and continually reminded
but not unexpectedly, this has also been accompanied during the course of treatment. Opioids should not be
by a concomitant and dramatic rise in the incidence used in isolation to treat pain and the goals of treat-
of diversion and abuse of these medications as well as ment will commonly require additional medications
the incidence of complications including overdosage such as anticonvulsants, antidepressants, NSAIDs, and
and death. other adjuvant treatments as well as nonpharmaco-
Currently, statistics show that approximately 90% logic strategies. While advocacy for appropriate opi-
of patients with chronic pain receive opioids (3-26), oid usage in chronic pain continues, it is well known
and 90% of patients presenting to an interventional that prolonged use of opioids may result in adverse
pain management center are already on opioids (27). consequences, including tolerance, hyperalgesia, hor-
It is estimated that the prevalence of a substance abuse monal effects, and immunosuppression.
disorder is 8.1% in the general population (28) and
even higher in the population of patients with chronic
Opioid Tolerance and Physical
Dependence
pain (20-26). These facts explain the dramatic rise in
prescription drug abuse and in complications second- Tolerance, a loss of analgesic potency, is one of
ary to controlled substances. One study showed that the common complications of opioid treatment, lead-
16% of active pain patients were found to be abusing ing to ever-increasing dose requirements and decreas-
their medications (21). In another study, Manchikanti ing effectiveness over time. Physical dependence is the
et al (22) reviewed the records of almost 5,500 pa- development of an altered physiological state that is
tients, and found 91 deaths, of which 18 were drug revealed by an opioid withdrawal syndrome involv-
poisoning deaths. Of those, 12 were felt to be partially ing autonomic and somatic hyperactivity. There are 2
or significantly due to prescription drugs. types of tolerance: innate (which is genetically deter-
Other side effects, such as constipation, nausea mined and would be present from the initial dose of
and vomiting, respiratory depression, and sedation the opioid) and acquired (pharmacokinetic, pharma-
often limit the dosing and effectiveness of opioids, codynamic, and learned) (29). Pharmacokinetic toler-
leading to early discontinuation, under-dosing, and ance results from changes in the metabolism of a drug
inadequate analgesia. Appropriate identification and after repeated administration, such as the induction
management of these side effects would be expected of an enzyme by the administration of the drug itself
to improve patient compliance and medication effi- (as seen with initiation of methadone treatment).
cacy and reduce complications. Pharmacodynamic tolerance is represented by the
For many years, the use of opioids for noncancer classic decreased effectiveness of an opioid over time,
pain was limited but this has changed secondary to related to up-regulation of receptors. Learned toler-
S106 www.painphysicianjournal.comOpioid Complications and Side Effects
ance, on the other hand, results in a decrease in effi- also striking that patients on chronic opioids such as
cacy as compensatory mechanisms are incorporated or methadone have dramatically decreased tolerance to
learned. For instance, a patient in a setting where he experimental pain (such as a cold pressor test) com-
or she usually consumes the drug typically expects the pared to patients on no opioids (20 seconds compared
drug to be less effective; however, if the same person to 1 minute), despite additional high doses of mor-
takes the same amount of drug in a nonstandard set- phine (34).
ting, he or she will likely feel a greater effect (30). In conclusion, although tolerance is a well known
One concern when starting a patient on long-term physiologic phenomena, its clinical relevance is un-
opioids has to be whether efficacy can be maintained known. Further studies to determine appropriate
over time. Both acute and chronic administration of methods to decrease its development and to deter-
opioids may produce tolerance as indicated by the mine its relevance are warranted.
lowering analgesic effects of the same dose over time.
Since the initial studies by Light and Torrance in the
Opioid-induced Immunologic Effects
1920s, the major focus on research for tolerance has The immunomodulatory effects of opioids were
been its relationship to physical and psychological de- initially demonstrated in the 1890s when Cantacuzene
pendence (31). Since tolerance was considered to be showed cellular immune suppression and decreased
the driving force to support the street addicts’ abuse resistance to bacterial infection in guinea pigs treated
of opioids, there was a notion that it would occur in a with morphine. Opioids have been implicated in the
similar way if opioids were used on a chronic basis in increased incidence of infections in heroin addicts and
patients with chronic pain. Physicians were reluctant as a cofactor in the pathogenesis of human immuno-
to use opioids and preferred to use them in a restric- deficiency virus. Interestingly, although exogenous
tive manner to preserve their efficacy for a situation opioids may generate immunosuppression, their en-
when they were really needed. However, there are no dogenous counterparts (e.g., endorphins), induce im-
studies to support this point of view. Interestingly, it munoactivation. It is known that acute and chronic
seems that tolerance develops at a different rate de- opioid administration can cause inhibitory effects on
pending on the specific opioid prescribed. antibody and cellular immune responses, natural killer
Although short-term studies have shown opioid cell activity, cytokine expression, and phagocytic activ-
efficacy for 4 to 32 weeks, it is not ethically possible to ity. The immunologic effects of opioids are mediated
do placebo controlled randomized opioid trials, so the by central and peripheral mechanisms. The potential
only knowledge of long-term analgesia comes from mechanism by which central opioid receptors mediate
surveys, case series, open-label studies, and epidemio- peripheral immunosuppression may involve the hy-
logic studies (32). When prescribing opioids, clinicians pothalamic-pituitary-adrenal axis and the autonomic
should be aware of the lack of complete cross toler- nervous system. Interestingly, peripheral immune cells
ance. That is, the development of tolerance to one under the influence of cytokines, may release endoge-
particular opioid doesn’t necessarily confer tolerance nous opioids modulating analgesia and inflammatory
to another. The clinical significance of this fact is para- responses. Moreover, the same cells can express opioid
mount, as prescription of a new opioid at equianalge- receptors, creating a bi-directional system whereby
sic doses may lead to overdose. opioids, immune cells, and cytokines dynamically in-
Recent evidence suggests that spinal adaptations teract (35-37).
leading to increased activity of sensory neuropeptides, The role of different central opioid receptors in
such as calcitonin gene-related peptide (CGRP) and the modulation of the immune response is variable
substance P, and their downstream signaling messen- (Table 1). Activation of KOR (kappa opioid receptor)
gers derived from metabolism of arachidonic acid such and DOR (delta opioid receptor) may activate the cel-
as prostaglandins (PG), lipoxygenase (LOX) metabo- lular immune response (38,39), while effects of MOR
lites, and endocannabinoids, play an important role in (mu opioid receptor) may be more related to natural
the tolerance phenomenon (33). killer (NK) cell activity, cytokine secretion, and macro-
In mice, NMDA receptor antagonists block the phage phagocytosis. Probably related to the affinity of
development of tolerance to morphine, but not fen- different opioids to a particular receptor is the finding
tanyl or a pure delta opioid receptor agonist; few that mice injected with morphine had a biphasic im-
similar studies in humans have been performed. It is mune response (40) with an increase in polymorpho-
www.painphysicianjournal.com S107Pain Physician 2008: Opioid Special Issue: 11:S105-S120
Table 1. Central immunologic effects of opioids. Table 2. Opioid-induced hormonal changes.
Receptor Effect Hormone Opioid Effect Potential symptom linkage
MOR Decreases NK cell activity (central) Testosterone decrease decreased libido
Macrophage phagocytosis (central) erectile dysfunction
Inhibits T-cell proliferation (central) reduced energy
Nitric oxide release (peripheral) Estrogen decrease sexual dysfunction
DOR Increases NK cell activity (central) reduced bone mineral density
Potentiates humoral immune response (MOR osteoporosis
dependent) Cortisol decrease secondary hormonal alterations
Decreases PFC response
Luetenizing decrease secondary reduced androgen
DOR At low dose inhibits DHR hormone hormone levels
antagonist amenorrhea
KOR Pronounced suppression of humoral immunity hypomenorrhea
KOR Increases PFC Gonadotropin decrease secondary reduced androgen
antagonist Suppression of humoral immune response releasing hormone levels
(MOR dependent) hormone
PFC=plaque forming cells; DHR=delayed hypersensitivity reaction; NK=natural
killer
nuclear phagocytosis, followed by a marked decrease and free) (41,47), estrogen (estradiol, etc.) (42,45-
24 hours later. Methadone, however, in an equianalge- 53), luteinizing hormone (LH) (42,53), gonadotrophin
sic dose did not affect the tested immunoparameters. releasing hormone (GnRH) (51,57,58), dehydroepi-
In clinical practice, not all opioids have similar effects androsterone (DHEA) and dehydroepiandrosterone
on the immune system. Particular reference needs to sulfates (DHEAS) (43), adrenocorticotropin (ACTH) and
be made to tramadol, which enhances NK cell activity, corticotropin-releasing hormone (CRH) (48,59), and
lymphocyte proliferation, and IL-2 release compared cortisol (48,59). The majority of work has focused on
to morphine, while buprenorphine, with its mu ago- the androgen hormones because of their linkage to
nist and kappa antagonist effects, doesn’t show any many symptomatic side effects of opioid usage.
effects on the immune response compared to mor- Many men who are taking prescribed or illicit opi-
phine. It is important to remark that severe pain by oids suffer from several side effects including sexual
itself has a significant immunosuppressive effect and dysfunction (i.e., erectile dysfunction, decreased li-
although the use of certain opioids may potentially in- bido, etc.), depression, and decreased energy level.
crease the risk of infection, the clinical significance of These unwanted side effects have been correlated to
this relationship between pain, analgesia, and opioid- hypogonadism and likely hypogonadotrophic hypo-
induced immunosuppression has not been clarified. gonadism (43,44,60,61). Testosterone levels are typi-
cally lowered 1 – 4 hours after acute administration
Opioid-induced Hormonal Changes of opioids (45) and return to normal levels within 24
The effects of opioid compounds on hormonal hours of stopping the opioid (62). Chronic administra-
function is now fairly well understood and has been tion of opioids for nonmalignant pain result in tonic
termed opioid endocrinopathy (OE) (Table 2) or, in the decreases in both total (TT) and free (FT) testosterone
case of androgen hormones, opioid-induced andro- levels in an apparent dose-dependent fashion (41,47).
gen deficiency (OPIAD) (41-43). The hormonal effects It should be noted, however, that not all men show
of opioid usage affect both men and women and have decreased TT levels and several physiological (e.g.,
been documented during oral consumption (41,43-47) Basal Metabolic Index) and behavioral measures (e.g.,
as well as transdermal (4,44-48), intravenous (49-52), smoking) may predispose individuals to hormonal side
and intrathecal (53,54) administration. OE has also effects of opioids (41). Also, it is not entirely clear that
been documented in illicit drug users where serum reduced testosterone directly contributes to sexual
hormone levels return to normal following withdraw- dysfunction. Through multivariate analyses Hallinan
al from the drug (45,49,55,56). Various studies have and colleagues concluded that testosterone levels
demonstrated opioid effects on a variety of hormones contributed little variance in measures of sexual dys-
including but not limited to testosterone (both total function (63). However, it should be noted that these
S108 www.painphysicianjournal.comOpioid Complications and Side Effects
data were obtained from addicts on methadone or fects of opioids to reduced bone mineral density. More-
buprenorphine maintenance treatment and may not over, while estrogen replacement therapy may be use-
entirely apply to patient populations taking opioids ful in some women to restore menses or maintain bone
for nonmalignant chronic pain. Studies examining mineral density in younger women, there have been no
potential adjuvant therapies treating potential hor- controlled studies weighing the benefits of such therapy
monally mediated side effects are rare. Daniell and against the well publicized risks associated with estro-
colleagues (44) performed an open-label trial of tes- gen replacement therapy.
tosterone replacement therapy in men taking opioids
for chronic noncancer related pain. Although many
Opioid-induced Hyperalgesia
men showed improvement in indexes of sexual func- Hyperalgesia (also referred to as hyperalgia) is a
tion, mood, and well-being, the effects were general- relatively new recognized adverse effect, and is gen-
ly incompletely resolved (44). Interestingly, the effects erally defined as an increased pain sensitivity (68).
of opioids on testosterone may be dependent on the This sensitization presents as increasing pain despite
specific opioid utilized. Bliesener and colleagues (47) increasing doses of opioids (69). Long-term use and
studied the hormonal effects of opioid maintenance high doses of opioids may be associated with the
and found that individuals taking buprenorphine had development of hyperalgesia, which may be related
significantly higher plasma testosterone levels and to opioid metabolites, such as morphine 3-glucero-
showed less sexual dysfunction compared to patients nide (M3G). Opioid-induced cell apoptosis may also
receiving methadone. be associated with hyperalgesia. The loss of GABA
Again, it is unclear if these results can be extrapo- neurons to apoptosis may result in changes in spinal
lated to pain patient populations, but it underscores neuronal circuits (70). NMDA receptor agonism also
the importance of a potential for medication depen- has a major role in the development of hyperalge-
dent hormonal side effects. Apart from circulating tes- sia, as does glycine, an inhibitory neurotransmitter
tosterone levels, adrenal androgens are also reduced that mediates the postsynaptic inhibition of spinal
in men on prescribed opioids (42,45,53). These latter neurons (71). At least in mice, the use of an L-type
findings suggest that opioids may not only affect hy- calcium channel blocker (amlodipine) prevented the
pothamic-pituitary-gonadal function but also hypo- hyperalgesia and tolerance of chronic morphine ad-
thalamic-pituitary-adrenal function as well. ministration (72). This is consistent with the concept
Women also experience similar hormonally linked that morphine-induced abnormal pain and antino-
side effects of opioids including depression, dysmen- ciceptive tolerance may be mediated by enhanced
orrhea, sexual dysfunction, and, potentially, reduced release of excitatory neurotransmitters (73). There
bone mineral density. Several studies have demon- are limited treatment options for the hyperalgesia
strated reduced estrogen levels in women on metha- and tolerance; in rats, ketamine (a NMDA antago-
done maintenance (42). nist) prevented fentanyl-induced hyperalgesia (74).
Reduced LH is also observed and appears to be more Recent studies in opioid addicts have helped to con-
pronounced in postmenopausal women. Interestingly, firm the clinical impression that chronic opioid use
testosterone levels also appear to be reduced in women results in an abnormal pain perception, consistent
taking prescribed opioids and may be related to body with hyperalgesia (75).
mass index and estrogen replacement therapy (64). The
direct consequences of reduced LH and progesterone
Opioid-induced Sedation
levels on dysmenorrhea are currently unclear. The sedating effects of opioids in opioid naïve pa-
The reductions in estrogen may have implications tients are fairly well known (76). Opioid-induced seda-
for osteoporosis and fractures in the older population. tion and drowsiness are thought to be caused by the
Ensrud and colleagues (64) found that, in a cohort of anticholinergic activity of opioids. Although tolerance
8,127 older women, patients that were taking opioids to these side effects often develops, dose initiation
had a greater risk for any nonspinal fracture. Some have and rapid dose escalation may result in sedation and
suggested that, in part, this relative increase in risk of consequently lead to noncompliance and/or reduced
fracture may be due to an androgen-based reduction in quality of life. The suggested treatments are opioid
bone density (65-67). While this is a plausible hypothesis, dose reduction, opioid rotation, and use of psychoso-
there is a lack of causal data connecting the hormonal ef- matic stimulants.
www.painphysicianjournal.com S109Pain Physician 2008: Opioid Special Issue: 11:S105-S120
Psychostimulants may improve psychomotor volunteers treated with IV morphine showed reduc-
performance scores and subjective drowsiness (77). tions in slow wave sleep and a mild decrease in REM,
Methylphenidate is the most common medication but no increase in awakenings or arousals (86). A ran-
investigated to treat opioid-induced sedation. In a domized, double-blind study (87) involving 42 healthy
double-blind randomized study of cancer patients re- volunteers given 5 mg methadone or 15 mg sustained
ceiving continuous subcutaneous opioids, a daily dose release morphine, showed that both opioids increased
of 10 mg methylphenidate significantly improved the the percentage of time spent in light sleep and sub-
mean baseline drowsiness scores by 35% compared stantially decreased (30% to 50%) the percentage of
with 8% in the placebo group (78). In another double- time in deep sleep (stages 3 and 4). No drug effects
blind, randomized study in cancer patients, 15 mg of were seen on sleep efficiency, total sleep time, wake
daily methylphenidate use led to a 61% improvement after sleep onset, or subjective measures of mood
in drowsiness score, with only 25% improvement in or fatigue. Both cortical arousal and the sleep-wake
the placebo group; at the same time, there was an cycles are regulated by converging inputs from the
associated decreased pain and decreased number of brainstem and pontinecholinergic projections (88).
opioid doses (79). A 15 mg daily dose of methylpheni- Sleep and waking is regulated by many neurotrans-
date was studied in a double-blind randomized fash- mitters, including noradrenaline, serotonin, acetyl-
ion in 32 cancer patients maintained on a steady dose choline, dopamine, histamine, gamma-aminobutyric
of oral opioids (80). The treatment group had a 61% acid (GABA), the pituitary hormones, and the neuro-
improvement in drowsiness score, which was signifi- hormone melatonin. Any drugs that alter the balance
cantly greater than 25% improvement in the placebo of these neurotransmitters, as opioids do, can poten-
group. Methylphenidate was also associated with de- tially affect sleep. Although the exact mechanism by
creased pain and rescue opioid doses. Multiple uncon- which opioids disrupt sleep is unclear, morphine has
trolled studies have also demonstrated positive results been shown to reduce REM sleep perhaps in part by
with methylphenidate. Although other options like modulating GABAergic signaling via inhibition of ace-
dextroamphetamine, donepezil, modafinil, and caf- tylcholine release in the medial pontine reticular for-
feine are also available, methylphenidate is the most mation. The resultant disruption of sleep architecture
widely studied agent, and in absence of side effects affects the states of arousal during wakefulness (89).
and abuse potential it should be considered as first In animals, REM suppression is associated with mu, but
line therapy (81). not kappa or delta opioid receptor agonists.
Opioid-induced Sleep Disturbances Psychomotor Performance in Opioid
Therapy
Sleep disturbance is common in cancer patients
(82). It is usually attributed to insomnia or pain, but The negative effects of opioids on psychomotor/
there is little evidence to support this. Arousal from driving performance in opioid naïve patients remains
sleep or disturbed sleep from pain has been reported controversial in the minds of clinicians — multiple stud-
but there is some evidence that patients in pain do ies support the notion that for many patients it is rea-
not suffer from disturbed sleep more than those not sonable to drive on a stable dose of opioids (76,90-92).
in pain. In addition, no correlation has been found When opioids are initially added to the management
between pain severity and sleep disturbance. The ef- of pain, patients’ abilities to operate heavy equipment
fect of opioids on sleep in palliative care patients has may be diminished and so they should not be allowed
not been well studied. Opioids are generally believed to drive automobiles; however, once a stable opioid an-
to enhance sleep but again, there is little evidence to algesic regimen is reached, patients with no significant
support this belief. cognitive/psychomotor impairments should be allowed
Opioids increase the number of shifts in sleep- to drive — as they would be allowed to drive with any
waking states (83), and decrease total sleep time, medication which can potentially cause central nervous
sleep efficiency (84), delta sleep, and REM sleep (85). system depression (e.g., antidepressants). In contrast,
However, in these studies, it is difficult to differentiate others believe that patients on stable doses of opioid
the effects of the opioid medication from the effects medications should be allowed to drive vehicles (93).
of the underlying disorders (e.g., cancer, addiction/de- Direct evidence provided in a subset of patients with
pendence, postoperative pain). A study of 7 healthy chronic pain on a stable opioid analgesic regimen (76)
S110 www.painphysicianjournal.comOpioid Complications and Side Effects
showed that these patients were capable of operat- up-regulation in the brain, but it does not up-regulate
ing automobiles safely during daytime, in normal cli- intestinal P-glycoprotein (101).
mate weather. A structured, evidence-based review Assessment of constipation can be difficult; a
by Fishbain et al (94) suggested that in opioid-depen- questionnaire (Patient Assessment of Constipation)
dent/tolerant patients on stable doses of opioids, no that measures symptom severity (PAC-SYM) and qual-
impairment of psychomotor abilities are observed even ity of life (PAC-QOL) can be used (102). The question-
immediately after a dose of opioid. naire was validated in chronic low back pain patients
and found to be a reliable, valid, and responsive mea-
Opioid-induced Constipation sure of the presence and severity of opioid-induced
Constipation is a common problem, occurring constipation symptoms.
in 40% to 95% of patients treated with opioids There is a need for effective treatment of opiate-
and can occur even with a single dose of morphine induced constipation. It is partially attenuated by us-
(95). Although often dismissed as a trivial side ef- ing different types of opioid compounds or routes of
fect, the long-term consequences of constipation administration or combining opioids with other medi-
can result in significant morbidity and mortality, cations. However, refractory constipation may still de-
with an adverse effect on patient quality of life. Se- velop and opioid antagonists may play an important
vere constipation can force patients to reduce the therapeutic role in this respect. Antagonizing the gas-
dose of the opioid, resulting in decreased analgesia. trointestinal mu receptors is the basis for many current
Chronic constipation can result in hemorrhoid for- investigational medications to treat opioid-induced
mation, rectal pain and burning, bowel obstruction, constipation.
and potential bowel rupture and death. Opioids A novel approach to management of opioid-
activate mu receptors in the gastrointestinal tract induced constipation involves blocking peripheral
responsible for gut motility (84) from a vascular dis- opioid receptors in the gut with opioid receptor
tribution as well as local application to the gut (96). antagonists with prokinetic activity. Two recently
Reported rates of constipation with spinal adminis- developed mureceptor antagonists, methylnaltrex-
tration of opioids vary, but in general it is thought one and alvimopan, are currently under review
that spinal opioid receptors do not affect intestinal (103). Methylnaltrexone is a quaternary derivative
motility and transit in humans (61,97). It is unclear of naltrexone with strong mureceptor affinity but
whether opioid-induced constipation in humans is no intrinsic agonist activity; it blocks the peripheral
predominantly centrally mediated or peripherally actions of opioids while sparing central analgesic
mediated. Morphine may act within the CNS to alter effects and reverses the gut-slowing action of mor-
autonomic outflow to the gut (98). Peripherally it phine. It is currently under late-stage clinical inves-
affects intestinal motility by a direct stimulation of tigation for the treatment of opioid-induced consti-
opioid receptors in the enteric nervous system (99). pation in patients with advanced illness. Alvimopan,
Loperamide, an opioid receptor agonist with limited a selective, competitive mureceptor antagonist with
ability to cross the blood brain barrier, is used clini- limited oral bioavailability, has been used to reduce
cally to treat diarrhea, suggesting that opioids have the length of postoperative ileus. A systematic re-
a more direct local constipating effect. view of available data shows proof of concept but
Unlike many of the other side effects of opioids does not conclusively demonstrate the efficacy of
(respiratory depression, nausea, sedation), consti- peripherally acting muopioid antagonists in manag-
pation is unlikely to improve over time, and there- ing opiate-related constipation (103).
fore must be anticipated, monitored, and addressed
throughout the opioid treatment course (100) (Table
Opioid-induced Bladder Dysfunction
3). It is suggested that tolerance may be linked to The risk of opioid-induced bladder dysfunction
certain subtypes of mu receptors that mediate vari- (i.e., difficulty voiding or frank urinary retention) is a
ous pharmacological actions (99). Tolerance develops significant problem in postoperative patients, but the
more readily to mu-1-dependent actions than to non- incidence has been difficult to estimate because many
mu-1-dependent actions. Another hypothesis suggests other factors can play a role. Two studies reported uri-
that development of tolerance requires P-glycopro- nary retention in 3.8% and 18.1% of patients receiving
tein up-regulation. Morphine induces P-glycoprotein opioids in the postoperative period (104,105). Urinary
www.painphysicianjournal.com S111Pain Physician 2008: Opioid Special Issue: 11:S105-S120
Table 3. Medications for treatment of chronic constipation.
Agent Formula/strength Adult dosage Side effects/complications
Bulk laxatives
Methylcellulose Powder: 2 g (mix with 8 oz liquid) One to 3 times Bulk mass may predispose inactive patients to
(Citrucel) Tablets: 500 mg (take with 8 oz liquid) daily obstruction. Most common side effect is increased
2 tablets up to 6 intestinal gas.
times daily
Polycarbophil Tablets: 625 mg 2 tablets 1 to 4 Bulk mass may predispose inactive patients to
(Fibercon) times daily 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 Capsules: 240 mg Once daily Ineffective unless adequate fluid intake. Ineffective as
(Surfak) sole agent in patients with decreased bowel motility.
Contra-indicated with mineral oil laxatives.
Docusate sodium Capsules: 50 or 100 mg 50 to 300 mg Ineffective unless adequate fluid intake. Ineffective as
(Colace) Liquid: 150 mg per 15 mL sole agent in patients with decreased bowel motility.
Syrup: 60 mg per 15 mL 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 Possible side effects include diarrhea and electrolyte
day 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 Liquid: 400 mg per 5 mL 30 to 60 mL once Possible side effects include diarrhea and electrolyte
(Milk of Magnesia) daily 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 Powder: 17 g (mix with 8 oz liquid) Once daily Side effects include abdominal pain, bloating,
3350 (Miralax) cramping, and increased intestinal gas. More severe
side effects include diarrhea and hives.
Sodium biphosphate Liquid: 45 mL, 90 mL (mix with 4 oz 20 to 45 mL daily Use with caution in patients on sodium restricted
(Phospho-Soda) water, then follow with 8 oz water) 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.
S112 www.painphysicianjournal.comOpioid Complications and Side Effects
Table 3. Continued.
Agent Formula/strength Adult dosage Side effects/complications
Cascara sagrada Liquid: 120 mL 5 mL once daily Side effects may include strong cramping in the
Tablets: 325 mg 1 tablet daily 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 Side effects can include abdominal pain or cramping,
daily 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 Side effects may include strong cramping and
or twice daily 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.
retention is much more likely to occur after epidural
Cardiac Effects of Opioids
injection of morphine rather than intravenous or in- The cardiac side effects of opioids are not very
tramuscular injection (106). The mechanism of urinary common. Morphine has been associated with hista-
retention is still not completely understood. Opioids mine release and consequent vasodilation and hypo-
are well known to decrease detrusor tone and the tension (109). This adverse effect is partially blocked by
force of contraction, decrease the sensation of fullness H1 antagonism but completely reversed by naloxone.
and urge to void, and inhibit the voiding reflex. They Parasympathetic stimulation may also contribute to
probably do not increase sphincter tone (107). These bradycardia. Recently, a syndrome of QT prolongation
effects are naloxone reversible. Animal and human and torsade des pointes (Tdp) has drawn some atten-
studies suggest a significant centrally mediated effect tion partially due to an increase in use of methadone
on the brain and spinal cord, although peripheral ef- for treatment of chronic pain (110,111). Mortality rate
fects at the bladder may also play a role. Rosow and due to Tdp could be as much as 17% (112) and there-
colleagues (108) demonstrated that opioid-induced fore it is prudent to monitor the EKG for presence of
changes in bladder function are due, in part, to a pe- QT prolongation in patients receiving methadone.
ripheral opioid effect and can be reversed by methyln- Methadone can block the human ether-a-go-go-
altrexone, a peripheral opioid antagonist indicating related-gene (hERG) channel causing QT prolongation
that peripheral mechanisms may play a role. and torsades de pointes ventricular tachycardia (113-
www.painphysicianjournal.com S113Pain Physician 2008: Opioid Special Issue: 11:S105-S120
115). The incidence of tachycardia-corrected QT pro- Adverse Effects of Specific Opioids
longation (QTc) of greater than 500 milliseconds was
found to be 16% among heroin addicts treated with This section explores both common and uncom-
methadone, and TdP occurred in 3.6% of that same mon specific complications of the administration of
group (116). The absolute QTc value of 500 ms has been several medications including codeine, hydrocodone,
known as a definite risk factor to develop Tdp. But, hydromorphone, oxycodone, oxymorphone, mor-
some have suggested that a QT prolongation of more phine, and fentanyl.
than 30 ms from the baseline should be considered clini- Codeine is commonly used in the postpartum pe-
cally significant, and more than 60 ms prolongation be- riod for pain associated with episiotomy and cesarean
yond baseline is a risk factor to develop Tdp (117,118). section. As most mothers initiate breastfeeding, the
The QTc prolongation by methadone has been attrib- safety of codeine and its pharmacologically active me-
uted to its (R)-enantiomer which has 50 times more an- tabolite, morphine, amongst breastfed infants is of
algesic potency than its (S)-enantiomer (119). Clinically primary concern. The American Academy of Pediatrics
significant QTc prolongation has been mostly observed lists codeine as compatible with breastfeeding. How-
in patients taking total daily doses of more than 40 mg ever, Koren et al (83) published a case of a full-term,
methadone (120). But in a recent retrospective review, breastfed infant who died in a manner consistent with
lower daily doses of 30 mg methadone were found morphine overdose. An explanation proposed was
to cause QTc prolongation, and Tdp was observed in that if the mother is an ultrarapid metabolizer of cyto-
patients receiving daily doses of 40–200 mg metha- chrome P450 2D6, she produces much more morphine
done. Significant correlation was observed between when taking codeine than most people do. Options to
QTc prolongation and patients receiving methadone reduce the risk include discontinuing codeine after 2
and CYP3A4 inhibitors like fluoxetine, clarithromycin, – 3 days of use and being aware of symptoms of po-
fluconazole, and valproate (116). The same report also tential opioid toxicity in both mothers and newborns.
identified hypokalemia and diminished liver function Hydrocodone/acetaminophen is one of the most
as other risk factors for developing QTc prolongation. commonly prescribed medications for both acute and
Previously in separate reports, other medications like chronic pain relief in the United States, and is effective
cocaine, tricyclic antidepressants, quinine, haloperidol, as both an antitussive and opioid analgesic. Common
droperidol, chlorpromazine, and erythromycin had adverse reactions to this medication combination in-
been implicated to cause QTc prolongation (Table 4). clude dizziness, nausea, vomiting, drowsiness, and eu-
An updated list of medications causing Tdp-VT can be phoria. Respiratory depression and mood disturbance
found at www.qtdrugs.org. are rare. As with all opioids, hydrocodone may lead to
The serious consequence of QTc prolongation has physical and psychological dependence. Hearing loss is
prompted some to recommend repeated surface EKGs an infrequently recognized side effect of hydrocodone
during the course of treatment with methadone, es- use, with only a few case reports to date. Friedman et
pecially when raising the dose and adding other medi- al (122) described 12 patients with profound hearing
cations like CYP3A4 inhibitors and also when hypoka- loss attributed to hydrocodone (4 were initially unilat-
lemia and diminished liver function are present (121). 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-
Table 4. Factors correlated with QT prolongation in methadone cal characteristics of 5 patients who presented with
use. progressive sensorineural hearing loss, suspected to be
due to chronic hydrocodone/acetaminophen use. The
• CYP3A4 inhibitors (e.g. fluoxetine, clarithromycin, fluconazole
and valproate) admitted hydrocodone dose ranged from 10 to 300 mg
per day. None responded to high dose steroids, and all
• Hypokalemia
responded to cochlear implant. The authors felt that
• Diminished liver function
genetic polymorphisms of the drug metabolizing en-
• Cocaine zymes CYP2D6 or CYP3D4 or associated comorbidities
• Tricyclic antidepressants such as hepatitis C may predispose certain individuals
• Haloperidol to adverse reactions to the drug. It is unclear whether
the hearing loss is due to the hydrocodone or the as-
• Droperidol
sociated acetaminophen.
S114 www.painphysicianjournal.comOpioid Complications and Side Effects
OROS hydromorphone is a controlled-release for- Further, this medication may aggravate seizures in pa-
mulation that uses an active osmotic system to deliver tients with seizure disorders, as all opioids can poten-
consistent levels of hydromorphone over 24 hours and tially lower the seizure threshold. Additionally, since
achieve rapid steady state concentrations. Wallace at el opioids may cause sphincter of Oddi spasm, plasma
(124) investigated the safety and efficacy of once-daily amylase and lipase levels may unexpectedly increase.
OROS hydromorphone in patients with moderate-to- Caution is warranted in patients with biliary tract dis-
severe chronic low back pain. The study involved 209 ease such as acute pancreatitis or cholelithiasis.
patients randomized to receive treatment in 15 North Oxycodone CR is a long-acting opioid used for the
American study centers. The most common side ef- treatment of noncancer pain. Portenoy et al (126) per-
fects included constipation (20.9%), nausea (19.8%), formed an open-label, uncontrolled, prospective lon-
vomiting (9.7%), headache (14.0%), and somnolence gitudinal investigation of outcomes associated with
(14.0%). Long-acting opioids usually cause similar ad- use of Oxycodone CR. The study provides evidence that
verse event profiles to short-acting agents, with the the greatest need for dose titration occurs during the
most frequent effects on the gastrointestinal and ner- first 3 months for most patients, after which further
vous systems. dose escalation is minimal. During the 3 year study,
Oxymorphone is an opioid specific for the mu re- the most common adverse events included constipa-
ceptor and is approved to treat both acute and chronic tion (15%) and nausea (12%). Other adverse events
pain. Chamberlin et al (125) described the pharmacol- included somnolence (8%), vomiting (7%), and de-
ogy, safety, efficacy, and usage of oral oxymorphone pression (2%). After the first 3 months, the incidence
for pain management. Unlike oxycodone, it does not of all the common adverse events except depression
bind the kappa opioid receptor. This medication un- declined substantially. The most serious adverse events
dergoes extensive hepatic metabolism and it is con- included chest pain and accidental injury. All patients
traindicated in patients with moderate to severe liver with chest pain had cardiac risk factors at the time of
impairment. However, there is no report of significant study entry and the accidental injuries reported were
CYP3A4, 2C9, or 2D6 drug interactions. The absence of mostly fractures.
CYP2D6 metabolism limits its potential to cause some Morphine is used for the treatment of noncan-
of the more common drug interactions via the CYP450 cer pain. Osteoarthritis is often treated with opioids
system. The elderly can experience a 40% increase in as NSAIDS may cause gastrointestinal injury as well as
plasma concentrations while renally impaired patients renal compromise. The efficacy and safety of several
may have a 57 – 65% increase in bioavailability. Food branded sustained release morphine medications has
can also increase the rate of absorption by as much been studied in randomized trials to be comparable to
as 50%, necessitating dosing either 1 hour before or generic sustained release morphine (127). Constipation
2 hours after a meal. Primary adverse side effects in- is one of the primary reasons for adverse event related
clude nausea, vomiting, pruritus, pyrexia, and consti- patient withdrawal in this study.
pation. Notably, the manufacturer lists nausea and py- Fentanyl is also used for the treatment of chronic
rexia as the most common (defined as >10%). Caution low back pain. The delivery systems include transder-
is also warranted with using oxymorphone with other mal, buccal tablet, and oral transmucosal prepara-
CNS depressants including opioids, general anesthet- tions. Allan et al (128) studied the use of transdermal
ics, antidepressants, phenothiazines, sedatives, and fentanyl (TDF) in strong opioid naïve patients with
hypnotics. The manufacturer also warns of confusion, chronic low back pain in an open, randomized, par-
disorientation, respiratory depression, apnea, and sei- allel group multicenter study. This study looked at
zures when oxymorphone is given with cimetidine. the efficacy and safety of TDF and sustained release
However, no cause and effect relationship is known or morphine (SRM) in strong opioid naïve patients with
given for this warning. Mixed agonist/antagonist an- chronic low back pain. Data from 680 patients studied
algesics (e.g., butorphanol, buprenorphine) can also over 13 months showed similar pain relief with both
reduce the medication’s efficacy and precipitate with- medications but TDF caused significantly less constipa-
drawal symptoms in patients who take oxymorphone. tion. Another study by Portenoy et al (129) studied the
Respiratory depression is also a concern and the medi- fentanyl buccal tablet (FBT) for relief of breakthrough
cation is prescribed with caution in patients with hy- pain in opioid-treated patients with chronic low back
poxia, hypercapnia, or decreased respiratory reserve. pain with a randomized, placebo-controlled study.
www.painphysicianjournal.com S115Pain Physician 2008: Opioid Special Issue: 11:S105-S120
FBT is a new formulation of fentanyl that enhances on placebo (134). The Cochrane review of opioids for
transbuccal drug delivery via an effervescent reaction. neuropathic pain (135) reported a majority of adverse
Currently it is FDA approved for cancer related break- events and withdrawals from 8 intermediate term
through pain. Adverse events were reported in 65% placebo controlled trials (130,136-141). Analysis of 4
of patients including nausea (19%), dizziness (13%), studies reviewed by the authors of the Cochrane re-
somnolence (9%), dysgeusia (8%), vomiting (6%), view (136,137,139,141) revealed that 23 (11%) of 212
and dry mouth (5%). Two patients experienced seri- patients withdrew because of adverse events during
ous adverse events during the study including diabetic opioid therapy versus 9 (4%) of 202 receiving placebo.
gastroparesis and accidental overdose resulting in Another study (142) reported adverse events on a VAS,
loss of consciousness. This patient took 4 of the 600 precluding determination of the numbers of affected
mcg tablets without explanation. He fully recovered participants. The most common adverse events were
after resuscitation with oxygen and admission to the nausea (33% opioid versus 9% control) and constipa-
hospital. This is an untoward opioid-related effect, tion (33% opioid versus 10% control), followed by
which may make this medication seem less attractive drowsiness (29% opioid versus 6% control), and vom-
for breakthrough back pain. The study did show FBT is iting (15% opioid versus 3% control).
generally well tolerated at doses of 100 – 800 mcg and With all opioids, respiratory depression and death
provides evidence that a rapid-onset opioid is useful are the most feared complications. From 1979 to 1990,
for pain not associated with cancer. unintentional drug poisoning death rates were on av-
erage 5.3% per year; however, from 1990 to 2002, the
Discussion rate increased to 18.1% per year. In that same time
Adverse events related to the opioids discussed period, the number of opioid analgesic poisonings on
above appear similar except for a few exceptions. In death certificates increased 91.2%, while heroin deaths
general, they appear to fall into 2 broad categories: increased only 12.4% and cocaine deaths 22.8%. The
nonlife-threatening and life-threatening. Hydroco- increase in deaths generally matched the increase in
done may cause sensorineural hearing loss due to pos- sales for each type of opioid.
sible genetic polymorphisms. Constipation and nausea Drug deaths from opioids are a serious and in-
are the most common adverse effects and also lead creasing issue. Effective patient compliance with ap-
to dropouts in controlled trials. Both constipation and propriate medical treatment programs are needed to
nausea occurred more often with opioid therapy com- prevent rare but life-threatening adverse events.
pared to treatment with tricyclic antidepressants in
the only study that compared these 2 treatments with
Conclusion
placebo in postherpetic neuralgia (130). Dellemijn et There is evidence that opioid medications can be
al (131) reported high incidence of sweating, anorex- effective in treating a variety of chronic pain condi-
ia, and clouded vision. Their study also assessed the se- tions but, like most pharmaceutical based therapies,
verity of adverse effects and found that the mean in- their use can be potentially accompanied by side ef-
tensity of adverse effects, particularly that of sedation, fects and complications. Despite the rise in serious
decreased gradually over 2 – 3 months. Tolerance may adverse events involving the use of opioids, includ-
not develop to the constipating effects of opioids, and ing death, these medications continue to be widely
so constipation should be treated early and effective- prescribed in the majority of patients suffering from
ly. Two RCTs on oral opioids (132,133) reported with- chronic pain. Proper prescribing practices as well as
drawal symptoms that occurred in 1 – 2% of patients. physician and patient education can help manage tol-
After the treatment period, drug craving was reported erance issues, adverse events, as well as common and
by 8.7% of patients on morphine compared with 4.3% uncommon side effects.
S116 www.painphysicianjournal.comOpioid Complications and Side Effects
References
1. Aragon-Poce F, Martinez-Fernandez E, long-term opioid therapy. Anesth Analg McManus CD. Prevalence of illicit drug
Marquez-Espinos C, Perez A, Mora R, 2003; 97:1097-1102. use among individuals with chronic pain
Torres LM. History of opium. Interna- 13. Kell M. Monitoring compliance with in the Commonwealth of Kentucky: An
tional Congress Series 2002; 1242:19- Oxy-Contin prescriptions in 14,712 pa- evaluation of patterns and trends. J Ky
21. tients treated in 127 outpatient pain Med Assoc 2005; 103:55-62.
2. Goodrich JT. History of spine surgery in centers. Pain Med 2005; 6:186-187. 26. Manchikanti L, Damron KS, Beyer CD,
the ancient and medieval worlds. Neu- 14. Chou R, Clark E, Helfand M. Compar- Pampati V. A comparative evaluation of
rosurg Focus 2004; 16:E2. ative efficacy and safety of long-act- illicit drug use in patients with or with-
ing oral opioids for chronic non-cancer out controlled substance abuse in in-
3. Trescot AM, Boswell MV, Atluri SL, Han-
pain: A systematic review. J Pain Symp- terventional pain management. Pain
sen HC, Deer TR, Abdi S, Jasper JF, Singh
tom Manage 2003; 26:1026-1048. Physician 2003; 6:281-285.
V, Jordan AE, Johnson BW, Cicala RS,
Dunbar EE, Helm II S, Varley KG, Such- 15. Kalso E, Edwards JE, Moore RA, Mc- 27. Manchikanti L, Damron KS, Mcmanus
dev PK, Swicegood JR, Calodney AK, Quay HJ. Opioids in chronic non-cancer CD. Patterns of illicit drug use and opi-
Ogoke BA, Minore WS, Manchikanti L. pain: Systematic review of efficacy and oid abuse in patients with chronic pain
Opioid guidelines in the management safety. Pain 2004; 112:372-380. at initial evaluation: A prospective, ob-
of chronic non-cancer pain. Pain Physi- servational study. Pain Physician 2004;
16. Von Korff M, Deyo RA. Potent opioids
cian 2006; 9:1-40. 7:431-437.
for chronic musculoskeletal pain: Fly-
4. Manchikanti L, Whitfield E, Pallone F. ing blind? Pain 2004; 109:207-209. 28. Substance Abuse and Mental Health
Evolution of the National All Schedules Services Administration (2006). Results
17. Breivik H. Opioids in chronic non-can-
Prescription Electronic Reporting Act from the 2005 National Survey on Drug
cer pain, indications and controversies.
(NASPER): A public law for balancing Use and Health: National Findings. (Of-
Eur J Pain 2005; 9:127-130.
treatment of pain and drug abuse and fice of Applied Studies, NSDUH Series
18. Luo X, Pietrobon R, Hey L. Patterns and H-30, DHHS Publication No. SMA 06-
diversion. Pain Physician 2005; 8:335- trends in opioid use among individu-
347. 4194). Rockville, MD. www.oas.samh
als with back pain in the United States. sa.gov/nsduh/2k5nsduh/2k5Results.
5. Manchikanti L. Prescription drug Spine 2004; 29:884-891. pdf.
abuse: What is being done to address 19. Caudill-Slosberg MA, Schwartz LM,
this new drug epidemic? Testimony be- 29. Collett BJ. Opioid tolerance: The clinical
Woloshin S. Office visits and analge- perspective. Br J Anaesth 1998; 81:58-
fore the Subcommittee on Criminal Jus- sic prescriptions for musculoskeletal
tice, Drug Policy, and Human Resourc- 68.
pain in US: 1980 vs. 2000. Pain 2004;
es. Pain Physician 2006; 9:287-321. 30. Cepeda-Benito A, Davis KW, Harraid JH.
109:514-519.
6. Manchikanti L. National drug control Associative and behavioral tolerance to
20. Manchikanti L, Cash KA, Damron KS, the analgesic effects of nicotine in rats:
policy and prescription drug abuse: Manchukonda R, Pampati V, McManus
Facts and fallacies. Pain Physician Tail flick and paw-lick assays. Psycho-
CD. Controlled substance abuse and il- pharmacology (Berl) 2005; 180:224-
2007; 10:399-424. licit drug use in chronic pain patients: 233.
7. Gajraj N, Hervias-Sanz M. Opiate abuse An evaluation of multiple variables.
or undertreatment? Clin J Pain 1998; 31. Light AB, Torrance EG. Opiate addic-
Pain Physician 2006; 9:215-225.
14:90-91. tion. VI: The effects of abrupt with-
21. Manchikanti L, Pampati V, Damron KS, drawal followed by readministration of
8. Simon S, Bennett D, Rauck R, Taylor D, Brandon DE, Cash KA, McManus CD. morphine in human addicts, with spe-
Shoemaker S. Prevalence and charac- Does random urine drug screening re- cial reference to the composition of the
teristics of breakthrough pain in non- duce illicit drug use in chroic pain pa- blood, the circulation and the metabo-
cancer patients with chronic neuro- tients receiving opioids? Pain Physi- lism. Arch Intern Med 1929; 44:1-16.
pathic pain. Pain Med 2005; 6:192. cian 2006; 9:123-129.
32. Ballantyne JC. Opioids for chronic pain:
9. Bennett D, Simon S, Rauck R, Taylor D, 22. Manchikanti KN, Manchikanti L, Damron Taking stock. Pain 2006; 125:3-4.
Shoemaker S. Prevalence and charac- KS, Pampati V, Fellows B. Death from
teristics of breakthrough pain in non- 33. Trang T, Quirion R, Jhamandas K. The
psychotherapeutic agents: An evalua-
cancer patients with chronic back pain. spinal basis of opioid tolerance and
tion in interventional pain management
Pain Med 2005; 6:193. physical dependence: Involvement of
practice. In submission; 2008.
calcitonin gene-related peptide, sub-
10. Fishbain DA, Rosomoff HL, Rosomoff 23. Manchikanti L, Damron KS, McManus stance p, and arachidonic acid-derived
RS. Drug abuse, dependence, and ad- CD, Barnhill RC. Patterns of illicit drug metabolites. Peptides 2005; 26:1346-
diction in chronic pain patients. Clin J use and opioid abuse in patients with 1355.
Pain 1992; 8:77-85. chronic pain at initial evaluation: A
34. Athanasos P, Smith CS, White JM, So-
11. Chabal C, Erjavec MK, Jacobson L, Mari- prospective, observational study. Pain
mogyi AA, Bochner F, Ling W. Metha-
ano A, Chaney E. Prescription opiate Physician 2004; 7:431-437.
done maintenance patients are cross-
abuse in chronic pain patients: Clinical 24. Manchikanti L, Pampati V, Damron KS, tolerant to the antinociceptive effects
criteria, incidence, and predictors. Clin Beyer CD, Barnhill RC, Fellows B. Prev- of very high plasma morphine concen-
J Pain 1997; 13:150-155. alence of prescription drug abuse and trations. Pain 2006; 120:267-275.
12. Katz NP, Sherburne S, Beach M, Rose dependency in patients with chronic
35. Stephanou A, Fitzharris P, Knight RA,
RJ, Vielguth J, Bradley J, Fanciullo GJ. pain in western Kentucky. J KY Med As-
Lightman SL. Characteristics and kinet-
Behavioral monitoring and urine tox- soc 2003; 101:511-517.
ics of proopiomelanocortin mRNA ex-
icology testing in patients receiving 25. Manchikanti L, Damron KS, Pampati V,
www.painphysicianjournal.com S117You can also read
