nausea y vomito inducidos por opioides que hacer

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Nausea and Vomiting Side Effects with Opioid Analgesics during

Treatment of Chronic Pain: Mechanisms, Implications, and

Management Optionspme_583 654..662

Frank Porreca, PhD, and Michael H. Ossipov, PhD

Department of Pharmacology, University of Arizona, Tuscon, Arizona, USA

A B S T R A C T

Objectives. Gastrointestinal (GI) side effects such as nausea and vomiting are common followingopioid analgesia and represent a significant cause of patient discomfort and treatment dissatisfac-tion. This review examines the mechanisms that produce these side effects, their impact on treat-ment outcomes in chronic pain patients, and counteractive strategies.

Results. A number of mechanisms by which opioids produce nausea and vomiting have beenidentified. These involve both central and peripheral sites including the vomiting center, chemore-ceptor trigger zones, cerebral cortex, and the vestibular apparatus of the brain, as well as the GI tractitself. Nausea and vomiting have a negative impact on treatment efficacy and successful patientmanagement because they limit the effective analgesic dosage that can be achieved and are fre-quently reported as the reason for discontinuation of opioid pain medication or missed doses. While

various strategies such as antiemetic agents or opioid switching can be employed to control theseside effects, neither option is ideal because they are not always effective and incur additional costsand inconvenience. Opioid-sparing analgesic agents may provide a further alternative to avoidnausea and vomiting due to their reduced reliance on mu-opioid signalling pathways to induceanalgesia.

Conclusions. Nausea and vomiting side effects limit the analgesic efficiency of current opioid thera-pies. There is a clear need for the development of improved opioid-based analgesics that mitigatethese intolerable effects.

Key Words. Chronic Pain; Opioids; Adverse Events; Nausea; Vomiting; Gastrointestinal

Introduction

C hronic pain is a debilitating condition affect-ing a significant proportion of the popula-tion. In Europe, one in five adults experienceschronic pain (as reported in the Pain in Europesurvey of 46,394 respondents) [1] and similarprevalence figures are reported in other popula-tions [25]. Yet, for a substantial number ofpatients, treatment appears to be unsatisfactory[1,68]. In accordance with the growing healthproblem represented by the management ofchronic pain conditions, the use of opioid analge-

sic treatment is expanding to include both malig-nant and nonmalignant chronic pain [9].

Although some patients can achieve sustainedpartial pain relief with opioid therapy withoutintolerable side effects [10], many patients are not

being treated adequately, for reasons that includeconcerns over tolerability, as well as with addic-tion issues [11] (although the risk of addiction inchronic pain is, at present, not well understood).

An important reason for the discontinuation ofopioid therapy is due to concerns over the toler-ability profile of this drug, particularly withstrong opioids such as morphine. The majorreasons for discontinuation of opioid analgesictreatment are gastrointestinal (GI) side effects(i.e., nausea, vomiting, and constipation) along

with central nervous system side effects [12]. The

Reprint requests to: Frank Porreca, PhD, Department ofPharmacology, LSN 562, University of Arizona, Tucson,AZ 85724, USA. Tel: 520-626-7421; Fax: 520-626-4182;E-mail: [email protected].

P A I N M E D I C I N E

Volume 10 Number 4 2009

American Academy of Pain Medicine 1526-2375/09/$15.00/654 654662 doi:10.1111/j.1526-4637.2009.00583.x
mailto:[email protected]:[email protected]


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incidence of nausea and vomiting reported inpatients treated with opioids for chronic pain in aclinical trial setting ranges from 10% to 50%[1316]. While other GI side effects of opioidssuch as constipation can be prevented and con-

trolled to some degree by various measures suchas laxatives, increased fiber consumption andstool softeners [11], nausea and vomiting effectsare more difficult to control fully in the majorityof patients [17]. Indeed, in some patients, painalone may cause nausea and vomiting. There is,therefore, a need for development of new analge-sic drugs with improved benefitrisk profiles forchronic pain management.

This article will review data on the reasons fornausea and vomiting associated with opioid use,

why these side effects present a problem for clini-

cians and patients, and options to improve theefficiency of opioid analgesics for use in chronicpain conditions. Medline literature searches wereperformed using a combination of the followingkeywords: nausea/vomiting and opioid and pain.

Articles included in this review were manuallyselected based on their relevance to nausea and

vomiting side effects experienced during opioidtreatment of chronic pain. Other references wereselected on an ad hoc basis to provide additionalsupport.

Mechanism of Emetogenic Effects

Various stimuli that lead to nausea and vomitingact on the vomiting center in the medulla oblon-gata of the brain. This center is not a discretelocus but rather consists of groups of loosely orga-nized neurones (sensory and motor control nucleilocated mainly in the medulla but also in the spinalcord), which can be activated in a co-ordinatedsequence [18]. Nausea and vomiting can be stimu-lated or repressed via chemoreceptors present inthe vomiting center [19], receiving inputs fromdifferent locations [20]. Nausea and vomiting areusually initiated by peripheral irritant stimuli

acting on the gastrointestinal tract, which aretransduced into sensory signals transmitted cen-trally to the vomiting center by vagal and sym-pathetic afferent nerves. However, the samesensations can be induced by direct stimulation ofparticular brain regions [21].

The vomiting center receives input from fourmajor areas: the chemoreceptor trigger zone(CTZ) for vomiting, the GI tract, the vestibularapparatus in the temporal lobe, and the cerebralcortex (Figure 1) [20]. Opioids exert emetogeniceffects through multiple mechanisms, principally

involving three of these areas, namely: directstimulation of the CTZ, inhibition of gut motility,and stimulation of the vestibular apparatus. Therole of the cortex in opioid-induced nausea isunclear, but may be related to a patient recallingprevious episodes of nausea and/or vomiting afteropioid therapy [20]. The effects are mediated viainteraction with specific opioid receptors (mu,delta, and kappa subtypes) in the brain and spinalcord and, in some circumstances, at peripheralsites [22,23].

Opioid Stimulation of the CTZThe neurons that make up the CTZ are foundwithin the area postrema at the floor of the fourthventricle. The permeability of the blood-brainbarrier at the CTZ means that these neurons maybe directly stimulated by many toxins, metabolitesor drugs, including opioids, that are present inthe systemic circulation [20]. The mechanism ofopioid-induced stimulation of the CTZ occurs viathe activation of opioid mu and delta receptors[24], and signaling to the vomiting center occursprimarily via dopamine D2 receptors as well as via

serotonin (5-HT3) receptors present in the CTZ[20]. Opioid-evoked emesis mediated via the CTZdecreases with repetitive opioid administration,

with the development of tolerance to emesis pos-sibly dependent on the type of opioid administered[2527].

Opioid Inhibition of Gut Motility

Central, as well as peripheral, opioid receptors areinvolved in inhibiting gut motility, but the pre-dominant mechanism appears to be via activationof mu receptors in the GI tract [28], leading to

Figure 1 Sensory input into the vomiting center of thebrain. D2 = D2 dopaminergic; 5-HT3 = serotonin type 3;H1 = histamine type 1; Achm = muscarinic acetylcholine.Adapted with permission from Herndon et al. [20].

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decreased GI transit via effects on the circular andlongitudinal muscles of the intestine involved inperistalsis. However, kappa receptor agonists havealso been shown to inhibit gut motility [29], and somay also play a role in this phenomenon. Signaling

to the vomiting center from the GI tract occursvia a serotonergic signaling pathway [20]. Opioidinhibition of gut motility can lead to distension ofthe gut, increased GI emptying time and consti-pation, resulting in stimulation of visceral mecha-noreceptors and chemoreceptors. This, in turn, isoften responsible for nausea and vomiting in ter-minally ill patients receiving opioid drugs [20].

Opioid Stimulation of the Vestibular Apparatus

The vestibular apparatus is located in the bonylabyrinth of the temporal lobe, and is responsible

for detecting changes in equilibrium. The vestibu-lar apparatus is stimulated directly by mostopioids, although the mechanism by which thisoccurs remains to be determined [20]. It has beenpostulated that mu receptors on the vestibular epi-thelium are responsible for opioid-induced stimu-lation of the vestibular apparatus [30], but kappaand delta receptors are also localized within theinner ear [31]. Sensory input to the vomitingcenter occurs via the histamine H1 and cholinergic

AChm pathways [19,20]. Emesis may be morecommon if patients are ambulatory, with nauseastimulated by rapid movement and dehydration[19].

The Complexity of Opioid Effects

The emetogenic mechanismsinvolved for a specificopioid depend on the specificity of an opioid formu, delta, or kappa receptors. Thus, for example,mu opioid receptor agonists have been associated

with nausea and vomiting, but kappa opioid recep-tor agonists may not be [32]. The clinical situationis often complicated by the variety of differentopioid-related emetogenic mechanisms. These can

vary from patient to patient, more than one may be

active in any one patient at the same time, and themechanisms may change from acute- to long-termopioid use. For example, emetogenic effects causedby medullary CTZ stimulation often decrease veryrapidly [22,27]. In some patients, however, nauseaand vomiting side effects are known to persistduring long-term treatment [33]. Furthermore,analgesic tolerance (a reduction in the pain-relieving effect of opioids) usually manifests overtime as multiple cellular and molecular adapta-tions take place, including neuroplastic changes[22,27,3436]. As a consequence, dose escalation is

common in order to maintain the same level of painrelief, but this is likely to enhance the risk of recur-ring nausea and vomiting as well as other sideeffects. Dose escalation must therefore be con-trolled in order to maintain opioid efficacy while

limiting the risk of adverse events [37].Conversely, higher doses of some opioids (such

as morphine) may actually reduce nausea and vom-iting by interacting with mu opioid receptors inthe vomiting center rather than the CTZ [38,39].

Thus, the relationship between opioid use andthe incidence of nausea and vomiting is complex.Other potential complicating factors include thechoice of opioid. Although the incidence of nauseaand vomiting appears to vary little with the type ofopioid analgesic used, some opioids have beenreported to induce less nausea and vomiting than

others [40], even at carefully controlled equianal-gesic doses [41]. For example, oral morphine wasassociated with a significantly greater incidence ofnausea than any other opioid or treatment modal-ity studied [41].

Implications for Clinicians and Patients

The Clinicians Perspective

From the clinicians perspective, it is important toidentify the underlying cause of nausea and vom-iting from among the multiple causative mecha-nisms for each patient so that effective treatmentcan be chosen (Table 1). Opioid stimulation ofthe CTZ leading to nausea and vomiting can betreated with dopamine receptor antagonists suchas phenothiazines (e.g., prochlorperazine) or buty-rophenones (e.g., haloperidol and droperidol),though dopamine antagonism with these agentscan cause a range of side effects such as drowsiness,constipation, dystonia, parkinsonism, tardivedyskinesia, torsades de pointes, and neurolepticmalignant syndrome [20,42,43]. Serotonin recep-tor antagonists (e.g., dolasetron, granisetron, and

ondansetron) are also effective for the preventionof nausea and vomiting caused by opioid stimula-tion of the CTZ, and are associated with a goodtolerability profile [17,20]. It is worth noting thatalthough these drugs have been approved by theFood and Drug Administration (FDA) for thetreatment of nausea and vomiting, they have notbeen specifically approved for opioid-inducednausea and vomiting.

Metoclopramide acts directly on the GI tractand is thus effective against nausea caused bygastric stasis [39] and is often considered to be the

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first-line therapy for opioid-induced nausea due

to its side-effect profile and mechanisms of action[20]. Thus, if nausea is associated with earlysatiety, bloating or postprandial vomiting, all of

which are signs of delayed gastric emptying, meto-clopramide is a reasonable initial treatment [13].

Metoclopramide reduces gut transit times throughenhancement of the acetylcholine response in theGI tract, and is thus beneficial to patients withnausea associated with constipation [20,44]. Meto-clopramide also inhibits peripheral dopamine andserotonin receptors and, additionally, appears toprovide D2-receptor inhibition in the CTZ athigh doses [20].

Several classes of agents are effective againstvestibular vertigo-like symptoms. Histamineantagonists (e.g., cyclizine) are active at the vom-iting center as well as the vestibular apparatus,

which make them valuable in the treatment ofnausea associated with movement or vertigo. Incontrast, anticholinergic drugs (e.g., scopolamine)exert an antiemetic effect via their inhibition ofacetylcholine signaling directly within the vomit-ing center [13,20,45,46]. Side effects associated

with antihistamines and anticholinergic agentsmay be bothersome (e.g., xerostomia, constipa-

tion, blurred vision, and confusion), but at lowdosages the drugs are generally well tolerated.

In some cases, a single antiemetic agent may besufficient to relieve nausea and vomiting, but thisis not always the case, and sometimes the combi-nation of more than one antiemetic may be nec-essary [43]. For example, the combined blockadeof dopamine and serotonin receptors by haloperi-dol and ondansetron, respectively, may sometimesbe required to relieve intractable nausea and vom-iting [43,47]. Alternative options include switch-ing to another antiemetic or an alternative opioid

[13,48], use of low doses of an opioid receptor

antagonist such as naloxone [49], as well as nonp-harmacological interventions. Nonpharmacologi-cal interventions include increased access to freshair, limiting dietary intake (e.g., avoiding sweet,salt, fatty, and spicy foods), providing distractions(e.g., talking, music, reading, etc.), and relaxationtechniques such as rhythmical breathing and posi-tive visual imagery [19].

Unfortunately, there is a lack of clinical trialdata concerning the use of antiemetics in patients

with opioid-induced nausea and vomiting, andeven these limited data are equivocal. A systematicreview of chronic pain therapy in 67 trials involv-ing 3,991 patients (with cancer pain or noncancerpain), identified seven studies and three casestudies of antiemetic agents, and showed a wide

variation in antiemetic efficacy, with many studiesof a very small size (four of the seven trials con-sisted of less than 20 patients) [43]. Moreover,a randomized, double-blind, placebo-controlledtrial of ondansetron and metoclopramide in 92patients failed to show a significant reduction inemesis in either treatment group compared withthose given placebo [50].

In addition to tolerability issues surrounding the

use of opioids, most antiemetics are associated withtheir own tolerability problems, as has been previ-ously noted [43]. Moreover, before the treatmentof opioid-induced nausea and vomiting can bestarted, other emetogenic drugs used in patients

with chronic pain (e.g., digoxin, antibiotics, iron,and cytoxics) should be tapered or discontinued ifpossible, which can cause further problems [43].

However, there have been recent developmentsin antiemetic therapy. For example, risperidone, anatypical antipsychotic thatblocks dopaminergic D2and serotonergic 5-HT2 receptors, has recently

Table 1 Drugs for treating nausea (used in a palliative care setting)

Drug Class Mechanism of Action Nausea Response

Butyrophenones (haloperidol, droperidol) D2 blockade in CTZ Chemical irritation,visceral

Phenothiazines and derivatives (chlorpromazine,

prochlorperazine, thiethylperazine)

D2 blockade in CTZ and GI tract Vestibular

Antihistamines (cyclizine, diphenhydramine,hydroxyzine, meclizine, promethazine)

H1 blockade in vomiting center and vestibular apparatus Vestibular

Anticholinergic agents (hyoscine, scopolamine) Muscarinic blockade in vomiting center and GI tract VestibularSerotonin antagonists (dolasetron, granisetron,

ondansetron)5-HT3 blockade in GI tract and CTZ Gastric stasis

Prokinetic agents (metoclopramide) D2 blockade in GI tract and CTZ; 5-HT4 stimulation inGI tract; 5-HT3 blockade in CTZ and GI tract(high dosages)

Gastric stasis

Benzodiazepines (lorazepam) GABA agonist Anticipatory nausea

D2 = D2 dopaminergic; CTZ = chemoreceptor trigger zone; GI = gastrointestinal; H1 = histamine type 1; 5-HT = serotonin; GABA = g-aminobutyric acid.Adapted with permission from Herndon et al. [20].



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been shown to be an effective antiemetic in thetreatment of refractory opioid-induced nauseaand vomiting in advanced cancer patients (N = 20)[51]. Furthermore, a randomized, double-blind,placebo-controlled trial showed that the use of low

doses of the opioid receptor antagonist naloxoneproved to be effective in reducing morphine-induced nausea in children and adolescents (N =46) without significantly affecting analgesia [49].

Overall, the evidence indicates that the sideeffects of opioid therapy in chronic pain patientssuch as nausea and vomitingrepresent a signifi-cant barrier to achieving effective pain control andpatient compliance. In a survey of 569 generalpractitioners in the United Kingdom, 74% citedpain medication side effects as a major barrier toeffective pain control in patients with chronic non-

cancer pain. In addition, 58% cited poor patientcompliance (also linked to tolerability), and 96%believed treatment could be improved [52].

The Patients Perspective

From the patients perspective, nausea and vomit-ing are among the most disturbing and distressingside effects that they experience [53]. Severalstudies have demonstrated the negative impact ofopioid-induced nausea and vomiting on patientfunctionality and quality of life outcomes [5456].

Moreover, nausea and vomiting are particularlycommon side effects in patients with chronic non-cancer pain taking opioid analgesics. The meta-analysis by Moore and McQuay, which included 34trials of opioid use in chronic noncancer paininvolving 5,546 patients, showed that dry mouth(25%), nausea (21%), and constipation (15%) werethe most common adverse events, with 22% ofpatients discontinuing treatment as a result of theseside effects [16]. A systematic review of random-ized, placebo-controlled trials of opioids for thetreatment of chronic noncancer pain showed thatnausea was reported in 32% and vomiting in 15%of patients (vs 12% and 3%, respectively, in those

given placebo) [57]. Thus, the relative risk (95%confidence interval [CI]) was 2.7 (2.13.6) fornausea and 6.1 (3.311.0) for vomiting in thesepatients.The rate of discontinuation due to adverseevents among patients receiving opioid was 24%(relative risk 1.4 [95% CI 1.11.9] vs placebo), and

just 44% were still on treatment at the end of studyfollow-up [57]. Furthermore, nausea and vomitingare not necessarily short-term effects, as shown bya 3-year U.S. registry study in which 219 patientsreceived long-term oxycodone (mean duration541.5 days; mean dose 52.5 38.5 mg/day) [33].

In this study, nausea and vomiting were reported by12% and 7% of patients, respectively [33]. In mostpatients, the reporting of side effects decreased

with the duration of therapy, but in minority ofcases, nausea and vomiting were still occurring

after 3 years [33].The side effects of medication for chronic pain

are of great concern to patients, as shown by aEuropean survey of patients with chronic pain [1].

Two-thirds of survey respondents were concernedabout the side effects of their pain medication [1].Similar concerns were expressed in the Road-blocks to Relief survey conducted by the AmericanPain Society [58]. Furthermore, patients often citenausea and vomiting as reasons for discontinuingtheir analgesic medication. In two comparativestudies of immediate-release and controlled-

release oxycodone given to patients with chronicnoncancer or cancer pain, the most frequentlycited reasons for treatment discontinuation amongthose with noncancer pain were nausea and

vomiting [59].

Cost Implications

Economic issues surrounding the cost implicationsof poor tolerability to opioid therapy for chronicpain are beginning to receive attention [56,6062].Drug costs form a small proportion of the totaleconomic burden, as the cost of medical personneltime typically forms more than 70% of total healthcare spent [60]. Nevertheless, the cost of managingnausea and vomiting associated with opioid treat-ment will incur additional drug acquisition costs forantiemetics, as well as health care staff time todiagnose, prescribe and administer these agents, inaddition to the cost of switching to another opioidif side effects become unmanageable [56,61,62].Other costs associated with poor tolerability ofopioids are those for additional pain relief (e.g.,

with non-opioid analgesics), as the tolerable doseof opioid may be limited by its side effects such as

nausea and vomiting [56,61,62]. Furthermore,these side effects can lead to poor treatment com-pliance and patients attitudes that their pain is notbeing treated effectively by their doctor (28% ofpatients in a European survey reported that theirdoctor did not know how to control their pain, and40% with chronic pain that their pain was not wellmanaged) [1], resulting in patients consulting onephysician after another in an attempt to seekimproved pain management. The costs incurred bynoncompliant behavior in chronic pain patientshave also been calculated [62,63].



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Improving the RiskBenefit Ratio ofOpioid AnalgesicsLittle research has been undertaken in recent

years to develop opioid-sparing analgesics withimproved riskbenefit profiles, despite the known

need for agents such as these. In some cases,opioid-sparing adjuvant analgesics are used toallow opioid dose reduction, but this is far from anideal solution [64]. However, nonpharmacologicalinterventions that specifically target cognitive pro-cesses may be effective in conjunction with anal-gesia for patients with chronic pain. Thus, a recentstudy of patients perception of chronic painshowed that treatment effects can be enhanced byinterventions that specifically target cognitive pro-cesses (i.e., a multidisciplinary program includingexercise, relaxation, pain education, sleep manage-

ment, and cognitive restructuring exercises) [65].Research has led to the development of severalnew types of opioid-based analgesic therapy, of

which, some have been specifically designed tolimit adverse events. Novel preparations ofopioids, such as the transdermal fentanyl patches,achieve controlled transcutaneous opioid deliveryby means of a fentanyl reservoir located behind arate-controlling membrane. Constipation, nausea,and vomiting remain the most frequent adverseevents with this system, although it has been asso-ciated with lower incidences of constipation whencompared with systemic applications of morphinein open-label studies [6669]. However, there

were no differences found between the incidencesof nausea and vomiting [66,68,70,71]. Whentransdermal delivery systems were evaluatedagainst orally and intrathecally delivered opioidsin a recent systematic review of long-term opioidtherapy for chronic noncancer pain, intrathecalopioids achieved the lowest rates of withdrawalsfrom clinical studies due to adverse events [72].However, it is worth noting that intrathecal drugdelivery is not practical for many patients.

One new therapeutic strategy has been to

develop peripherally acting opioid receptorantagonists in order to selectively inhibit periph-eral mu opioid receptors in the GI tract withoutreversing centrally mediated opioid-induced anal-gesia. Two new peripherally acting mu opioidantagonists, alvimopan and methylnaltrexone,have recently been approved by the FDA forthe reduction of opioid-induced bowel dysfunc-tion associated with opioid analgesics [73,74].

Although results of preliminary studies are prom-ising, a recent systematic review of these agents forthe relief of opioid-related constipation concluded

that there are, as yet, not enough data to deter-mine whether or not they are effective for thispurpose [75]. One concern, however, is that anti-emetic agents with a restricted ability to cross theblood-brain barrier may have a reduced efficacy

against nausea and vomiting mediated throughcentral mechanisms. Also under current investiga-tion are oral fixed combinations of opioid receptoragonists and antagonists such as prolonged-releaseoxycodone and naloxone, as well as oxycodoneand naltrexone [76,77]. These drugs are similarlydesigned to reduce peripheral GI side effects bytheir peripheral inhibitory action on gut opioidreceptors [78]. However, although these agentshave a low systemic bioavailability, a negativeimpact on the analgesic effects of the combinationproducts by the antagonist component cannot be

excluded [79]. The combination potentially offersless dosing flexibility than the use of separateantagonists.

A novel approach is to combine more than oneanalgesic principle in one molecule so that bothmechanisms are pharmacologically engaged. Thisconcept was realized in tapentadol, a compoundpurposely designed to combine two analgesicactions, mu opioid receptor agonist activity withnorepinephrine reuptake inhibition. In this case,the analgesic effect is not reliant solely on agonistactivity at the mu receptor that is also responsiblefor side effects. Data from preclinical studies indi-cate that the combination of these two analgesicactions is less likely to produce opioid-mediatedside effects; for example, in one of the most com-monly used emesis model species, the ferret [80],tapentadol may produce fewer episodes of retch-ing and vomiting as compared with morphine [81].

This suggests a potential therapeutic advantageover the currently available classical opioid anal-gesics, offering improved tolerability and equiva-lent analgesic efficacy.

Conclusions

In conclusion, opioids cause nausea and vomitingin many patients through multiple and complexcausative mechanisms. Nausea and vomitingare common side effects of opioid analgesia, andare distressing to patients, leading to a significantreduction in their quality of life. These types of sideeffect are often difficult to treat, can be persistent,and are major causes of noncompliance with painreliefmedication. Moreover, addressing suchprob-lems is associated with a cost burden to health careservices. New approaches designed to address the



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cleartherapeutic need may offerpotential solutionsto improve analgesic efficiency while diminishingthe potential for adverse effects, especially nauseaand vomiting, which lead to inadequate pain relief.

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