www.medigraphic.org.mx CONFERENCIAS MAGISTRALES Opioids for the treatment of non-cancer pain
* Professor of Anesthesiology and Medicine. Vice-Chair for Clinical Affairs. Department of Anesthesiology,
University at Buffalo. Chief, Pain Medicine and Professor of Oncology. Roswell Park Cancer Institute. INTRODUCTION
gested by the WHO step ladder, portending that it may not be appropriate to treat every patient in the same way. Thus, the
The analgesic ladder was introduced under the auspices of role and the place of opioid therapy in chronic non-cancer pain the World Health Organization (WHO) in 1990(1) with the are better defi ned in the 21st century. Likewise the potential idea of providing health care providers around the world with
complications associated with long-term opioid therapy are
a tool to help them implement pain therapy in patients with
cancer related pain. With the suggestion that opioids could
To facilitate the presentation of the arguments, the discus-
also be used for the treatment of non-cancer related pain(2),
sion will be divided accordingly in distinct clinical conditions
the principles of the analgesic ladder were eventually imple-
where most of the literature has become relevant to support
mented in patients with non-cancer pain(3). Moreover, recent
studies have addressed the potential problems associated with the use of non-steroidal anti-infl ammatories (NSAIDs) and
PATIENTS WITH OSTEOARTHRITIS (OA)
cyclo-oxygenase-2 (COX-2) inhibitors in the geriatric popu-lation, expanding the indications for opioids in the treatment
The fi rst line agent for the treatment of pain associated with
of non-cancer pain. The objective of this review is to discuss
osteoarthritis is acetaminophen(13). However, as the disease
the fi ndings of recent articles published in the literature sug-
progresses, patients will eventually not respond to this form
gesting that the implementation of opioid therapy in patients
of therapy and will need a stronger analgesic for the control
with specifi c co-morbidities and drug-drug interactions may
of pain. According to the analgesic ladder, the choice would
be indicated to avoid signifi cant complications and adverse be a non-steroidal anti-infl ammatory (NSAID), or a cyclo-drug reactions. In fact, adverse drug reactions have been re-
oxygenase (COX-2) inhibitor. Well established contraindica-
cently linked to polypharmacy(4) and are estimated to incur tions to the use these drugs are renal failure(14) and a history costs in excess of one billion US Dollars annually just in or current evidence of peptic disease(15). There is a wide the United States(5). Since 28% of adverse drug events are understanding among clinicians of this fact. The incidence of preventable and occur most commonly with cardiovascular renal dysfunction is the highest in patients 65 years or older; drugs, diuretics, opioid analgesics, antidiabetic agents and it is dose-related to NSAIDs and COXIBs; ibuprofen, indo-anticoagulants(6), there is also a negative economic impact of
methacin, piroxicam are likely to be worse when compared to
using inappropriate medications in some patients.
other NSAIDs; pre-existing evidence of renal disease or gout
In parallel with these fi ndings, the availability of new increases the odds ratio of renal failure to 6; and the combina-
modes of delivery, such as topical analgesics(7), the develop-
tion of pre-existing renal disease and gout increase the odds
ment of clinical guidelines for the management of special ratio of renal failure to 82(14). Consequently, the use of these conditions, such as neuropathic pain(8-10), and the develop-
agents in the presence of renal dysfunction is ill advised.
ment, and the subsequent critical evaluation of interventional
Patients with PUD receiving NSAIDs will have an inci-
techniques for the management of pain such as neuromodula-
dence of upper gastrointestinal (UGI) ulcer complications
tion(11,12), etc., have signifi cantly change the approach sug-
2.9 times greater than those receiving celecoxib, and 2 times
Este artículo puede ser consultado en versión completa en http://www.medigraphic.com/rma
Volumen 35, Suplemento 1, abril-junio 2012
de Leon-Casasola OA. Opioids for the treatment of non-cancer pain
greater incidence of complications and symptomatic ulcers signifi cant lower incidence of complications and symptomatic than those treated with the same COX-2 inhibitor(15). More-
ulcers (4.7 versus 6%, p = 0.49) than those treated with non-
over, risk factors for the development of ulcer complications
specifi c NSAIDs(9). In the case of lumiracoxib(21), there were
also differences in the cumulative one year incidence of peptic ulcer complications between patients receiving lumiracoxib
• History of perforation, ulcer, or bleeding
only or non-specifi c NSAID (naproxen or ibuprofen) (0.20
versus 0.92%) and those who received lumirocoxib + ASA or
non-specifi c NSAID (0.69 versus 0.88%). The clinical impli-
cations of these fi ndings are important as the OA population
tends to be 65 years or older, and as a result of that will be
frequently receiving mini dose ASA for cardiovascular pro-phylaxis. Thus, one has the option to switch them from ASA to
In contrast, it is not as widely recognized that the inci-
clopidrogel or ticlopidine and then start therapy with a COX-2
dence of congestive heart failure (CHF) in patients 65 years
inhibitor, to use topical NSAID therapy (diclofenac)(22,23), or
or older who have a history of heart disease is just as high as
to implement therapy directly with either a short-acting opioid
the incidence of UGI peptic ulcer complications(17,18). The if the patient only needs one or two doses of this medication incidence appears to be the highest with the use of piroxicam,
per day, or a long-acting opioids(24,25) if more frequent dosing
naproxen, and tenoxicam(18). In fact, when these NSAIDs are
of a short-acting opioid is necessary.
used in patients with a history of heart disease, the odds ratio
Consequently, the WHO analgesic ladder oversimplifi es
of developing CHF is 25(19). Consequently, patients with either
the management of OA pain in patients with complex co-
chronic renal failure or increased plasma creatinine levels, morbidities which are typically present in the population af-those with a history of PUD or heart disease should not be fected by this disease. Additionally, the use of topical NSAIDs treated with NSAIDs. In contrast, it appears that celecoxib is not part of the algorithm as this form of therapy did not could be used in those patients with a history of heart disease,
exist when the guidelines were drafted. These two situations
as the incidence of CHF after one year of treatment, in a make the analgesic ladder obsolete and even dangerous in large scale observational study, was no different than those
in the control group(19). However, the risk of thromboembolic phenomenon and myocardial infarction is still a concern,
The other clinical situation to consider in patients with OA
Current guidelines for the treatment of peripheral neuropathic
is the co-administration of a mini-dose of aspirin (ASA) and
pain(8-10) suggest the implementation of therapy with topical
NSAIDs or COX-2 inhibitors. There is evidence that suggests
lidocaine as the fi rst step. If this is not successful, and there
that the co-administration of ASA and ibuprofen may result in
is not a contraindication for the use of a tricyclic antidepres-
acetylation of the serine 529 residue in the platelet that results
sant (TCA), the addition of one of these agents is suggested.
in >95% inhibition of thromboxane A2 (TXA2) production Alternatively, a dual re-uptake norepinephrine/serotonine and with this phenomenon, the loss of the anti-aggregation inhibitor may be used. If this combination is still not suc-effect of ASA in the platelets(20). It is not clear if this drug-drug
cessful, then the use of an anticonvulsant is suggested, and if
interaction may also occur with other NSAIDs, but al least in
despite the use of these three agents at maximum doses is not
theory, based on the mechanism of action, this could occur.
successful, then the use of an opioid or tramadol is suggested.
Moreover, there is evidence that co-administering a mini-dose
Current guidelines for the management of central pain suggest
of ASA and celecoxib(15) or lumirocoxib(21) may result in the
following the same algorithm as that outlined for peripheral
loss of the gastro-protective effects of COX-2 inhibitors. In
neuropathic pain, with the exception that topical lidocaine is
the case of celecoxib(15), patients not concomitantly receiv-
ing ASA and celecoxib 400 mg twice daily had a statistically
Consequently, the use of multiple adjuvants in the treat-
cant lower incidence of upper gastrointestinal (UGI) ment of neuropathic pain is indicated prior to implementing
complications than those treated with non-specifi c NSAID
therapy with opioids, but they are recognized as an important
(naproxen 800 mg TID or diclofenac 75 mg BID) (0.44 component of a treatment plan. There is no data to suggest versus 1.27%, p = 0.04) and a signifi cant lower incidence of
which opioid should be used when needed in these patients.
complications and symptomatic ulcers (1.4 versus 2.91%, p =
There have been suggestions, based on putative mechanisms
0.02). In contrast, patients who received ASA and celecoxib
of action, that tramadol, tapentadol, or methadone would be
400 mg twice daily did not have neither a lower incidence better choices, but this superiority has not been demonstrated of UGI complications (2.01 versus 2.12%, p = 0.92) nor a in randomized clinical trials.
de Leon-Casasola OA. Opioids for the treatment of non-cancer painIMPLEMENTING THERAPY
all other drugs are compared. Despite its clinical utility, the associated side effects led to attempts to develop molecules
Understanding the pharmacokinetics and pharmacodynamics
with similar analgesic action without the management chal-
of opioids is imperative to providing patients with effective
lenges(29). Over the last hundred years, numerous opiate drugs
pain relief and avoiding adverse effects, such as sedation, have been synthesized and the vast majority falls into the nausea, and vomiting. The clinician’s efforts should be di-
mu category; ie, they target the mu opioid receptor (MOR).
rected at producing opioid plasma concentrations within the
Initially, all mu opioids were thought to act through a single
therapeutic window to avoid side effects that occur when drug
class of opioid receptors, but subsequent research has identi-
concentrations rise above those necessary for pain relief and
fi ed genetic locations for several mu opioid receptor subtypes.
loss of effi cacy when plasma levels are too low(26). It is recom-
To date, at least 25 variants of the mu receptor have been
mended to try to open the therapeutic window to decrease the
identifi ed in mice, 8 in rats, and 11 in humans(30). Although
incidence of sedation, nausea and vomiting that may occur in
mu opioids share many pharmacological characteristics, there
up to 30% of the patient when fi rst exposed to opioid therapy
by prescribing a small dose of a long-acting opioid and then
The concept of multiple mu receptors may help explain
allowing the patient free access to a short-acting opioid(26).
the variability in individual response to various opioids, the
After two weeks of therapy, acute tolerance will typically de-
differences in side effects among patients, incomplete cross
velop, and with that, the therapeutic window widens, allowing
tolerance among various mu opioid analgesics, and the clinical
patients to tolerate higher doses of controlled released opioids
utility of opioid rotation(3,26,28). Opioid rotation is now a widely
with a lower incidence of these side effects(26).
accepted approach to poorly responsive pain patients in whom a neuropathic pain component has been adequately treated or
ruled out. If side effects with one opioid are signifi cant, an improved balance between analgesia and side effects might
Breakthrough pain is defi ned as a transitory increase of more
be achieved by changing to an equivalent dose of an alternate
severe pain over relatively well-controlled baseline pain(27,28).
opioid(26). Rotation between 2 or 3 opioids is often required to
The reported incidence of breakthrough pain ranges between
obtain satisfactory long-term pain control(31). A systematic re-
16% and 95% in patients with persistent pain(28). There are three
view of existing literature on opioid rotation performed in 2006
types of breakthrough pain: end-of-dose failure, incidental pain,
found that opioid switching results in clinical improvements
and spontaneous/idiopathic pain(28). End-of-dose failure occurs
in greater than 50% of patients with chronic pain who experi-
when plasma concentrations fall below the therapeutic window.
ence a poor response to one opioid(32). However, an important
In order to avoid end-of-dose failure, the dosing interval should
problem raised in the opioid literature is the conversion rate
be decreased. It is important to talk to patients about patterns
among the various opioid medications. Most conversion data
of breakthrough pain in relation to the time of administration
presented in reference tables are derived from older studies
of the long-acting opioid to determine if end-of-dose failure is
that were not designed for determining relative potencies(32).
responsible for the appearance of breakthrough pain.
Yet, an understanding of equianalgesic doses is important
Incidental and «true» breakthrough pain both occur despite
when both titrating long-acting opioids and performing opioid
appropriate opioid plasma concentrations. True breakthrough
rotations. One practical approach is the «rule of 2»(26) (Table
pain rises quickly in intensity and it is severe, occurring in I). Assuming a morphine dose of 100 mg/24 h and dividing patients whose pain was previously well controlled. It usually
it by two, one arrives at a dose equivalent of 50 mg/24 h for
lasts between 30 and 45 minutes before subsiding. A medication
oxycodone/hydrocodone. Dividing it by four, one reaches
with a rapid onset of action such as oral transmucosal fentanyl
the fentanyl (25 μg/h) and oxymorphone (25 mg/24 h) dose
or a fentanyl buccal tablet is needed to control this type of equivalents. Dividing it by eight, one obtains the equianalgesic pain, assuming that the pain is somatic in nature. In contrast,
dose of 12 mg/24 h for hydromorphone. This method allows
if the pain is neuropathic, it is unlikely that these alternative therapeutic options will be useful. Overall, when dealing with
www.medigraphic.org.mx Table I. Equianalgesic doses: Rule of two
breakthrough pain, it is important to determine fi rst, whether
(Based on a morphine dose of 100 mg/24 h)(26).
the pain is somatic, visceral or neuropathic, and then if it is due to end-of-dose failure or incidental and treat appropriately. OPIOID ROTATION
The largest groups of opioids are the morphine-like agonists.
Morphine remains a prototypic opioid analgesic against which
Volumen 35, Suplemento 1, abril-junio 2012
de Leon-Casasola OA. Opioids for the treatment of non-cancer pain
for relatively quick conversions. Although on the conservative
or the gel form. However, reduced sex hormones are more
side, these quick conversions should place the patient’s plasma
problematic in women because of the increased risk of breast
levels in the therapeutic range. However, the patient should be
cancer after estrogen/progesterone replacement. Thus, a con-
contacted within a day or two to determine if further titration
sult with an endocrinologist may be warranted to address the
is required. Although methadone is a very effective, and in-
risk of osteoporosis with the use of bisulphonates, calcium
expensive, medication, it provides a unique challenge because
there are no good dosing guidelines and no easy conversion
Opioid abuse and diversion:Based on the 2003 position
rates(32,33). Although there are several conversion protocols for
paper from the College on Problems of Drug Dependence,
methadone, for patients on a moderate opioid dose (400 mg of
there is a «need to strike a balance between risk management
morphine), we usually convert to 10 mg of methadone every 8
strategies to prevent and deter prescription opioid abuse
hours for the fi rst two weeks of treatment and then titrate the
and the need for physicians and patients to have appropri-
dose, based on pain scores, psychosocial functioning, rescue
ate access to opioid pharmaceuticals for the treatment of
opioid use, etc. If the patient is on higher opioid doses, the pain»(38). Although opioids should be a tool in the analgesic starting methadone dose is 20 mg every 8 hours. Patients on
armamentarium, it is essential that all health care providers
methadone need to be monitored closely. One study found a
approach pain management using opioids with the necessary
correlation between the daily dose of methadone and the QTc
due diligence, including a complete initial evaluation, fol-
interval in 17 patients who experienced torsade de pointes(34).
lowed by appropriate monitoring (random urine testing), and
Of note, the relationship persisted after adjusting for the clinical
documentation throughout treatment. At the outset of therapy
variables known to be associated with QT-segment prolonga-
with opioids, obtaining a signed agreement should be con-
tion. In patients who receive methadone doses greater than sidered wherein the patient’s expectations and the clinician’s 100 mg per day, it is imperative that baseline EKG testing be
performed and then repeated every 3 months(26). In addition,
Likewise, universal precautions should be implemented
if patients are receiving medications known to prolong the for other drug with a misuse potential such as certain anti-QTc segment, a consideration to switch to a different opioid
depressants and psychotropic agents (i.e., benzodiazepines).
Misuse includes usage of inappropriate drug combinations
In November 2006, the FDA released an alert about this
due to poor patient education or misinformation, as well as
information (FDA, 2006). The alert resulted in the addition
abuse and diversion. Appropriate education in an understand-
of a black box warning to the product labeling for methadone
able vernacular is essential to successful pain management.
manufactured as Dolophine® Hydrochloride CII (Roxane A strong predictor of the potential to opioid misuse is other Laboratories, Columbus, OH).
medication misuse, or alcohol and/or illicit drug abuse(39).
Este documento es elaborado por Medigraphic
Because patient reporting of both prescribed and other drugs
IMPORTANT CONSIDERATIONS IN THE
is highly unreliable at best, and because in the United Stated,
LONG-TERM USE OF OPIOIDS
43% of patients on long-term opioid therapy misuse their medications, routine urine toxicity screens for a wide range
There are four long-term concerns with the use of opioids: of substances are considered the cornerstone of pharmaco-endocrine changes, opioid abuse and diversion, those related
logical vigilance at this point(39,40). When opioid therapy is
to the central effects and metabolism of these agents, and initiated, and there is a high index of suspicion for opioid opioid-induced hyperalgesia.
abuse, a baseline urine drug screen can be used to assess if
Endocrine changes:Long-term opioid use decreases there has been any drug misuse, even before opioid therapy
cortisol levels, which may be why patients experience las-
is begun. Evaluations of patients should also involve noting
situde and lack of energy after long periods of therapy. It and documenting slurred speech, sleeping, or weaving while is important not to confuse these symptoms with those seen
walking, including observations gathered before the patient
when opioid therapy is implemented acutely(26). The diagno-
has even entered the examination room.
sis is made by performing an adrenocorticotropin (ACTH)
Using tools to interview and collect observations of patients
are another important strategy to monitoring and documenting
sideration to withdrawing opioid therapy or implementing a patient’s management with opioids (Table II). Screening corticosteroid replacement therapy is indicated. Additionally,
tools can provide information that can lead to the detection of
opioids decrease prolactin, luteinizing hormone (LH), follicle
early warning signs of drug misuse and indicate the need for
stimulating hormone (FSH), testosterone, and estrogen levels,
more thorough monitoring and in-person patient interactions.
which in turn can cause sexual impotence and eventually These instruments can help indicate which patients may be osteoporosis(3,36,37). This problem can easily be overcome more prone to non-adherence to therapeutic protocols, as well in men by prescribing testosterone in either intramuscular as to demonstrate due diligence in monitoring prescription
de Leon-Casasola OA. Opioids for the treatment of non-cancer painTable II. Tools for assessing drug misuse potential.
poor stress management and deteriorating work and/or home environments. These patients often self-medicate to «deal»
with their stressors, as well as to control their pain. In fact,
• Aberrant behaviors identified by clinicians according to a long-term follow-up study, patients with high
PMQ scores were 2.6 times more likely to have a known
• Checklist of risk behaviors (Chabal, Erjavec, et al,
substance-abuse problem, 3.2 times more likely to request
early refi lls of prescription medications, and 2.3 times more
• Prescription drug use questionnaire (PDUQ;
likely to drop out of treatment than patients with initially low
• Physician opioid therapy questionnaire (POTQ;
PMQ scores(45). Furthermore, patients who completed an
interdisciplinary pain management program had signifi cantly
• Addiction behaviors checklist (ABC; Wu et al, lower PMQ scores 6 months following discharge, compared to 2006)
those patients who discontinued the treatment. Patients with
PMQ scores over 32.83 should be closely monitored, as they
• The screening tool for addiction risk (STAR; Fried-
have a high potential for misusing controlled substances. The
PMQ can be a good resource that can be combined with other
• The screening instrument for substance abuse assessment techniques in order to gather a full understanding
of a chronic pain patient, leading to better individualization
• Screener and opioid assessment for patients with pain (SOAPP; Butler et al, 2004)
of therapy, and ultimately, better outcomes.
• Opioid risk tool (ORT; Webster & Webster, 2005)
Other important considerations:The use of morphine
• Current opioid misuse measure (COMM; Butler et
in patients with severe renal or hepatic insuffi ciency is not
advisable because they may experience myoclonus and/or
• Pain medication questionnaire (PMQ; Adams et
hyperalgesia due to morphine-3-glucoronide (M3G) accumu-
lation. M3G, in contrast to the other metabolite of morphine,
morphine-6-glucoronide (M6G), is neurotoxic(26).
Moreover, opioids in general should be used with caution
in patients with Addison’s disease, hypothyroidism, prostatic
use for potential US Food and Drug Administration audits. hypertrophy, or urethral stricture, and in elderly or debilitated In addition, the results from these tools, such as the Pain patients(26). Medication Questionnaire (PMQ), can be used to tailor the
Another important consideration when administering opi-
treatment program to the specifi c needs of patients. Still, they
oids is the effect on cognitive function(31). Side effects such
can be limited by their time-consuming nature, psychometric
as sedation, dizziness, and mental clouding interfere with
(un)reliability, and specifi city for only one type of alcohol or
activities that demand alertness, especially driving. Although
drug abuse (i.e., non-generalizable results).
driving is not advisable at the beginning of treatment, studies
The variety of pain medication questionnaires available have shown that cognitive function, including the ability to
is listed in table II. For example, chronic pain patients being
drive and operate machinery is often adequate in patients tak-
considered for long-term opioid therapy can be administered
ing stable, moderate doses of opioids for chronic pain(46,47).
the Screener and Opioid Assessment for Patients with Pain
When indicated and an opioid drug regimen is chosen, it is
(SOAPP) or the Opioid Risk Tool (ORT) to screen for sub-
important to be cognizant of the potential for drug-drug inter-
stance abuse potential(41,42). The SOAPP is a 14-item tool with
actions, as many opioids are metabolized by the enzymes that
established reliability and predictive validity. Alternatively,
modify and break down 40 to 50% of all medications. These
the Diagnosis, Intractability, Risk, and Effi cacy (DIRE) score
are the cytochrome P450 (CYP450) isoenzymes, and those
can be used to predict whether a chronic non-cancer pain primarily involved with opioid metabolism are the CYP2D6, patient will achieve effective analgesia and adhere to a long-
CYP2B6 (methadone), and CYP3A4 (fentanyl) systems(48,49).
term opioid maintenance treatment regimen(43).
Tramadol, oxycodone, hydrocodone, and codeine are con-
The PMQ is another self-report measure that can be verted to active metabolites by CYP2D6. Therefore, drugs that
administered quickly to broadly survey a patient’s misuse inhibit this enzyme will decrease their effects(50,51). In addi-potential for a range of pain medication types prescribed tion, other commonly used medications, including fl uoxetine, for chronic pain. Higher PMQ scores have a positive asso-
haloperidol, and paroxetine, can inhibit CYP2D6 function
ciation with measures of substance abuse, psychopathology,
resulting in a lack of pain relief(52). In constrast, morphine,
and physical/life-functioning(44); in other words, high-risk hydromorphone, and oxymorphone are not metabolized by the patients tend to have diffi culties controlling their medication
CYP450 enzymes, and therefore, can generally be prescribed
use concurrent with signifi cant psychosocial issues, such as
with medications metabolized by that enzyme family(50).
Volumen 35, Suplemento 1, abril-junio 2012
de Leon-Casasola OA. Opioids for the treatment of non-cancer painOpioid induced hyperalgesia: Sustained exposure to mented(56-58). For advanced severe cases of opioid-induced
opioids may result in increase sensitivity to pain, potentially
hyperalgesia, high-dose intravenous dexamethasone (a load-
by enhancing the descending facilitatory infl uence of the ing dose of 20 mg, followed by a course of 6-8 mg every 6 brain on pain transmission at the spinal cord level(53). This hours for a week) can be used effectively alongside other phenomenon, known as opioid-induced hyperalgesia, can adjuvant therapies and acetaminophen, while progressively be an outcome of very aggressive opioid dose titration(54).
tapering opioid doses. Dexamethasone decreases neuropep-
Likewise, the perioperative use of remifentanyl and fentanyl
tides, such as calcitonin gene-related peptide (CGRP) and
have been shown to have a higher risk, but all opioids, even
substance P, that are involved in neurogenic infl ammation and
methadone, have the capacity to induce this phenomenon opioid-induced hyperalgesia, and it induces the production when rapidly titrated to higher doses in patients with chronic
of kynurenic acid, a post-synaptic NMDA antagonist(56,57).
pain(55). Pronociception may also result from spinal sensiti-zation due to inappropriate increased brainstem excitatory
infl uences, involving spinal cholecystokinin and dynorphin, descending facilitation of the glutamatergic system, and sub-
Not all patients respond to analgesic regimens, including
stance P wind-up (increased central sensitization in response
opioid treatments. For these select patients, the following
to sustained input from nociceptive afferents)(53-55).
clinical scenarios should be considered and their treatment
Clinically, it is very important to distinguish between correspondingly adjusted: opioid tolerance, opioid-induced
opioid tolerance and opioid-induced pain sensitivity because,
hyperalgesia, an alternative disease processes such as myo-
despite having similar presentations, they require opposite fascial pain, and opioid misuse. Additionally, each patient’s management approaches(55). In both cases, patients present unique genetic background can infl uence the effectiveness with worsening pain. However, in the case of opioid-induced
and side effects of an analgesic regimen. Therefore, therapies
hyperalgesia, the pain intensity is increased above the level of
need to be individualized for each patient in order to maximize
the preexisting pain, despite the absence of disease progres-
opioid analgesic effects and minimize side effects, including
sion while opioid doses are titrated up(55). Also, with opioid-
discontinuing or rotating opioids when appropriate. Given the
induced hyperalgesia, the pain is more diffuse, often affecting
potential for metabolic issues and drug interactions, and the
areas beyond the original pain distribution. Managing opioid
availability of multiple analgesic options, when prescribing
tolerance with a trial of opioid dose escalation can appropri-
opioids it is also important to use strategies that minimize drug
ately control the pain, whereas opioid-induced hyperalgesia
interactions. Especially for individuals on multidrug regimens,
can be exacerbated with increasing opioid doses(55). In the such as older adults, an opioid that is not metabolized by the latter case, opioid doses should be signifi cantly reduced and
P450 enzyme system, such as morphine, hydromorphone or
acetaminophen and dexamethasone therapy should be imple-
oxymorphone, may be more suitable than other choices. REFERENCES
1. Schug SA, Zech D, Dorr U. Cancer pain management according to
10. Acevedo JC, Amaya A, de León Casasola OA, et al. Guías para el di-
WHO analgesic guidelines. Journal of Pain & Symptom Management
agnóstico y el manejo del dolor neuropático: Consenso de un grupo de
expertos latinoamericanos. Rev. Iberoamericana del Dolor 2008;3:15-46.
2. Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-
11. North R, Shipley J. Practice parameters for the use of spinal cord
malignant pain: Report of 38 cases. Pain 1986;25:171-186.
stimulation in the treatment of chronic neuropathic pain. Pain Medicine
3. Ballantyne JD, Mao J. Opioid therapy for chronic pain. N Eng J Med
12. Turner JA, Sears JM, Loesser JD. Programmable intrathecal opioid
4. Nguyen JK, Fouts MM, Kotabe SE, Lo E. The American Journal of
delivery systems for chronic non-cancer pain: A systematic review of
Geriatric Pharmacotherapy 2006;4:36-41.
effectiveness and complications. Clin J Pain 2007;23:180-195.
Johnson JA, Bootman JL. Archives of Internal Medicine 1995;155:1949-1956.
13. Eccles M, Freemantle N, Mason J. North of England evidence based
6. Zarowitz BJ, Stebelsky LA, Muma BK, Romain TM, Peterson EL.
guideline development project: summary guideline for non-steroidal
anti-infl ammatory drugs versus basic analgesia in treating the pain of
7. de Leon-Casasola OA. Multimodal approaches to the treatment of
degenerative arthritis. The North of England Non-Steroidal Anti-Infl am-
neuropathic pain: The role of topical analgesia. J Pain Symp Manag
matory Drug Guideline Development Group. BMJ 1998;317:526-530.
14. Bratter DC. Effects of nonsteroidals anti-infl ammatory drugs on renal
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm
function: focus on cyclooxigenase-2 selective inhibition. American
for neuropathic pain treatment: An evidence based proposal. Pain
Journal of Medicine 1999;107:65S-70S.
FE, Faich F, Goldstein JL, et al. Gastrointestinal toxicity with
9. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic man-
celecoxib versus nonsteroidal anti-infl ammatory drugs for osteoarthritis
agement of neuropathic pain: Evidence-based recommendations. Pain
and rheumatoid arthritis. The CLASS study-a randomized controlled
de Leon-Casasola OA. Opioids for the treatment of non-cancer pain
16. Laine L. Approaches to nonsteroidal anti-infl ammatory drug use in the
38. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug
high-risk patient. Gastroenterology 2001;120:594-606.
Dependence taskforce on prescription opioid non-medical use and abuse:
17. Page J, Henry D. Consumption of NSAIDs and the development of
position statement. Drug Alcohol Depend 2003;69(3):215-232.
congestive heart failure in elderly patients: an under recognized public
39. Turk DC, Swanson KS, Gatchel RJ. Predicting opioid misuse by chronic
health problem. Arch Int Med 2000;160:777-84.
pain patients: a systematic review and literature synthesis. Clin J Pain
J, Broms K, Lindblad U, et al. Association of outpatient utilization
of non-steroidal anti-infl ammatory drugs and hospitalized heart failure
40. Katz N, Fanciullo GJ. Role of urine toxicology testing in the manage-
in the entire Swedish population. Eur J Clin Pharmacol 2001;57:71-5.
ment of chronic opioid therapy. Clin J Pain 2002;18(4 Suppl):S76-82.
19. Mamdani M, Juurlink DN, Lee DS, et al. Cyclooxygenase 2 inhibitors
41. Butler SF, Budman SH, Fernandez K, et al. Validation of a screener
versus non-selective non-steroidal anti-infl ammatory drugs and conges-
and opioid assessment measure for patients with chronic pain. Pain
tive heart failure outcomes in elderly patients: a population-based cohort
42. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-
20. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibi-
treated patients: preliminary validation of the Opioid Risk Tool. Pain
tors and the antiplatelet effects of aspirin. N Eng J Med 2001;345:1809-
43. Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: predicting
21. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib
outcomes of opioid prescribing for chronic pain. J Pain 2006;7:671-681.
with naproxen and ibuprofen in the therapeutic arthritis research and
44. Adams LL, Gatchel RJ, Robinson RC, et al. Development of a self-report
gastrointestinal event trial (TARGET), reduction in ulcer complications:
screening instrument for assessing potential opioid medication misuse
randomized controlled trial. Lancet 2004;364:665-674.
in chronic pain patients. J Pain Symptom Manage 2004;27:440-459.
22. Anonymus. Diclofenac gel – Topical NSAIDs science. Drug and Thera-
45. Holmes CP, Gatchel RJ, Adams LL, et al. An opioid screening instru-
ment: long-term evaluation of the utility of the pain medication question-
23. Bruhlmann P, Michael BA. Topical diclofenac patch in patients with
knee osteoarthritis: a randomized, double-blind, controlled clinical trial.
46. Bruera E, Macmillan K, Hanson J, MacDonald RN. The cognitive effects
Clinical & Experimental Rheumatology 2003;21:193-198.
of the administration of narcotic analgesics in patients with cancer pain.
24. Caldwell JR. Avinza-24 h sustained release oral morphine therapy.
Expert Opinion on Pharmacotherapy 2004;5:469-472.
47. Vainio A, Ollila J, Matikainen E, Rosenberg P, Kalso E. Driving abil-
25. Matsumoto AK. Oral extended-release oxymorphone: A new choice for
ity in cancer patients receiving long-term morphine analgesia. Lancet
chronic pain relief. Expert Opinion on Pharmacotherapy 2007;8:151-157.
26. de Leon-Casasola OA. Implementing therapy with opioids in patients
48. Rogers JF, Nafziger AN, Bertino JS, Jr. Pharmacogenetics affects dos-
with cancer. Oncology Nursing Forum 2008;35(6):S1-6.
ing, effi cacy, and toxicity of cytochrome P450-metabolized drugs. Am
27. Caraceni A, Martini C, Zecca E. Breakthrough pain characteristics and
syndromes in patients with cancer pain. An international survey. Pal-
A, Totah P, Sheffels TR, et al. Role of CYP2B6 in stereoselective
human methadone metabolism. Anesthesiology 2008;108:363–74.
28. Payne R. Recognition and diagnosis of breakthrough pain. PainMedicine
50. Kadiev E, Patel V, Rad P, et al. Role of pharmacogenetics in variable
response to drugs: focus on opioids. Expert Opin Drug Metab Toxicol
29. Pasternak GW. Insights into mu opioid pharmacology. The role of mu
opioid receptor subtypes. Life Sciences 2001;68:2213-2219.
51. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype
30. Pasternak GW. The pharmacology of mu analgesics: From patients to
on postoperative tramadol analgesia. Pain 2003;105(1-2):231-238.
genes. Neuroscientist 2001;7:220-231.
52. Supernaw RB. CYP2D6 and the effi cacy of codeine and codeine-like
31. McNicol E, Horowicz–Mehler N, Fisk RA, Bennett K, Gialeli-Goudas
drugs. American Journal of Pain Management 2001;11:30-31.
M, Chew PW, et al. Management of opioid side effects in cancer-related
53. Suzuki R, Porreca F, Dickenson AH. Evidence for spinal dorsal horn
and chronic noncancer pain: A systematic review. The Journal of Pain
hyperexcitability in rats following sustained morphine exposure. Neu-
32. Mercandante S, Bruera E. Opioid switching: A systematic and critical
54. Mercadante S, Ferrera P, Villari P, et al. Hyperalgesia: an emerging
review. Cancer Treatment Reviews 2006;32:304-315.
iatrogenic syndrome. J Pain Symptom Manage 2003;26:769-775.
33. Mercandante S. Opioid rotation for cancer pain. Cancer 1999;86:1856-
J. Opioid-induced abnormal pain sensitivity: implications in clinical
opioid therapy. Pain 2002;100:213-217.
34. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects
56. Hong D, Byers MR, Oswald RJ. Dexamethasone treatment reduces
of methadone on QT prolongation in a series of patients with torsade de
sensory neuropeptides and nerve sprouting reactions in injured teeth.
pointes. Pharmacotherapy 2003;23:802-805.
35. Harris JD, de Leon-Casasola OA. Oral erythromycin and the risk of
57. Marek P, Ben-Eliyahu S, Vaccarino AL, et al. Delayed application of
sudden death. N. Eng J Med 2005;352:301-304.
MK-801 attenuates development of morphine tolerance in rats. Brain
36. Mendelson JH, Mendelson JE, Patch VD. Plasma testosterone levels
in heroin addiction and during methadone maintenance. Journal of
58. Stockler M, Vardy J, Pillai A, et al. Acetaminophen (paracetamol)
Pharmacology and Experimental Therapeutics 1975;192:211-217.
improves pain and well-being in people with advanced cancer already
Daniell HW. Hypogonadism in men consuming sustained-action oral
receiving a strong opioid regimen: a randomized, double-blind, placebo-
opioids. Journal of Pain 2002;3:377-384.
controlled cross-over trial. J Clin Oncol 2004;22:3389-3394.
Volumen 35, Suplemento 1, abril-junio 2012
GILDA SANDRI Dati personali Nazionalità: Italiana Data di nascita: 19/05/1967 Luogo di nascita: Roma Residenza: Fabbrico Reggio Emilia Via G. Matteotti n° 57/b 1986: Diploma di maturità Classica conseguito presso il Liceo Istruzione Ginnasio Virgilio di Mantova. 23/10/1992 Diploma di Laurea in Medicina e Chirurgia presso l’ Università degli studi di Modena con votazion