Melvin C. Gitlin

Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution?

Abstract Objective: Opioids are among the most effective and potent analgesics currently available. Their utility in the management of pain associated with cancer, acute injury, or surgery is well recognized. However, extending the application of opioids to the management of chronic non-cancer pain has met with considerable resistance. This resistance is due in part to concerns related to gastrointestinal and central nervous system-related adverse events as well as issues pertaining to regulatory affairs, the development of tolerance, incorrect drug usage, and addiction. This review focuses on the incidence of opioid-related side effects and the patient and physician barriers to opioid therapy for chronic non-cancer pain. Tapentadol, a centrally acting analgesic with two mechanisms of action, µ-opioid agonism and norepinephrine reuptake inhibition, may be considered to be a partial solution to some of these issues. Methods: MEDLINE was searched for English-language articles from 1950 to February 2010 using the terms chronic non-cancer pain and opioids together and in combination with undertreatment, adherence, and compliance. Results: The majority of patients treated with traditional opioids experience gastrointestinal- or central nervous system-related adverse events, most commonly constipation, nausea, and somnolence. These side effects often lead to discontinuation of opioid therapy. Concerns about side effects, analgesic tolerance, dependence, and addiction limit the use of opioids for the management of chronic pain. Treatment with tapentadol appears to provide several advantages of an analgesic with a more favorable side-effect profile than the classic µ-opioid receptor agonist oxycodone (especially related to gastrointestinal tolerability). Conclusions: The pervasiveness of opioid-associated side effects and concerns related to tolerance, dependence, and addiction present potential barriers to the approval and use of opioids for the management of chronic non-cancer pain. The lower incidence of opioid-associated adverse events and possibly fewer withdrawal symptoms, combined with a satisfactory analgesic profile associated with tapentadol, suggest its potential utility for the management of chronic non-cancer pain. This review will focus on the incidence of opioid-related side effects and barriers to opioid therapy that are available as English-language articles in the MEDLINE index, and as such, it is a representative but not an exhaustive review of the current literature.

The serotonin syndrome in a patient receiving sertraline after an ankle block

Sertraline is a new antidepressant categorized as a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) (1).This class of drugs reversibly blocks the reuptake of 5-HT in the synaptic cleft (1). Sertraline is efficacious in the treatment of depression, obsessive-compulsive, eating, and personality disorders (2). It is safe and well tolerated based upon worldwide experience (3). We report, however, a case of prolonged myoclonus in a patient who underwent a minor orthopedic procedure under an ankle regional anesthetic block and sedation and who was taking sertraline for depression. We propose that she exhibited the serotonin syndrome, a disorder of 5-HT hyperstimulation, most commonly associated with serotonergic drugs (4).

CYP2D6 poor metabolizer genotype and smoking predict severe postoperative pain in female patients on arrival to the recovery room.

UNLABELLEDnRecent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. The present study assessed the contribution of CYP2D6 genetic polymorphisms, smoking, and other factors on acute severe postoperative pain (linear analog pain scores ≥8).nnnMETHODSnTwo hundred thirty-six female patients were found to have adequate information in a previously developed female surgical patient database to be included in this current analysis. Multiple logistic regression analysis was used to assess the predictors for acute severe postoperative pain. DNA had been previously extracted from blood samples in all patients and was genotyped by the Amplichip to determine the specific CYP2D6 genotypes.nnnRESULTSnIt was noted that the incidence of acute severe postoperative pain (linear analog pain scores ≥8) was more frequent in patients with the CYP2D6 poor metabolizer (PM) genotype, 71%, compared with 28% in intermediate metabolizers (IMs), 26% in extensive metabolizers (EMs), and 27% in ultrarapid metabolizers (UMs). The overall association between metabolizer groups and severe postoperative pain was significant (P=0.023). PMs were significantly more likely to suffer from severe postoperative pain than IMs, EMs, and UMs (P=0.007, 0.002, and 0.050, respectively). There were no significant differences among IMs, EMs, and UMs. Additionally, it was noted that there was an increased frequency of acute severe postoperative pain in smokers vs nonsmokers (P=0.014).nnnCONCLUSIONnThis study demonstrated that female patients possessing the PM genotype of CYP2D6 and patients who smoke had a higher incidence of acute severe postoperative pain.

Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption

BACKGROUNDnThe interleukin-1 receptor antagonist (IL-1Ra) is the principal determinant of IL-1β bioactivity within the IL-1 gene cluster, regulating IL-1α and IL-1β release. This study was designed to determine whether polymorphisms of the IL-1Ra gene (IL1RN) produce clinically measurable differences in serum IL-1Ra concentrations and opioid consumption in the postoperative period.nnnMETHODSnOpioid consumption and pain scores were evaluated in 96 patients undergoing a nephrectomy. DNA was extracted from all patients, and the genotypes of IL1RN were determined by polymerase chain reaction amplification of the variable number of tandem repeats of 86 base pairs in intron 2 of IL1RN. The concentrations of serum IL-1Ra concentrations at baseline and at 24 h postoperatively in 58 subjects were measured.nnnRESULTSnDifferences in opioid consumption among the three genotype groups (IL1RN*1 homozygotes and *2 and *3 carriers) were statistically significant in the first and second 12-h postoperative periods (P = 0.010). The IL1RN*2 carrier group consumed 43% (95% CI, 38-48%) less opioids in the first 24 h after surgery than the IL1RN*1 homozygote group (P = 0.003). Differences in the serum IL-1Ra concentration among the three genotype groups were statistically significant at 24 h postoperatively (P = 0.003), with IL1RN*2 carriers having the highest serum IL-1Ra concentrations.nnnCONCLUSIONSnThe variable number of tandem repeats in intron 2 of IL1RN may contribute to interindividual variations in opioid consumption in the first 24 h after surgery. Patients homozygous for the IL1RN*1 allele have lower concentrations of IL-1Ra and require higher doses of opioids postoperatively than patients carrying at least one IL1RN*2 allele.

The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption.

BACKGROUNDnEndogenous morphine-like compounds have been identified in humans and are released in response to stress. Human monocytes and granulocytes express the micro opiate receptor, micro3, which is morphine selective but opiate peptide insensitive. Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. We theorized that ultrarapid (UM) CYP2D6 metabolizers may have an enhancement of their endogenous pain modulating mechanisms.nnnMETHODSnAfter institutional review board approval, a previously developed surgical patient database was evaluated for information concerning CYP2D6 genotypes and morphine consumption. One hundred forty-two patients were found to have adequate information to be included in this current analysis. The study group was divided, based on morphine consumption, into two subgroups: low morphine consumers (LMC) (< or =10 mg/4 h, N = 80) and high morphine consumers (HMC) (>10 mg/4 h, N = 62). DNA was extracted from blood in all patients and was genotyped by the Amplichip (Roche, Pleasanton, CA) to determine the specific CYP2D6 genotypes.nnnRESULTSnCYP2D6 UM were found to occur more frequently in the LMC group than in the HMC group (8/80 vs 0/62, P = 0.0091). No significant differences were noted for the poor, intermediate, or extensive metabolizers.nnnCONCLUSIONSnOur current results suggest that CYP2D6 UM appear to require less morphine in the acute postoperative period compared with other CYP2D6 metabolizer groups. One possible mechanism for this observation is that CYP2D6 UM may have higher efficiency in synthesizing endogenous morphine compared with other metabolizers, thus increasing endogenous pain modulation and reducing the need for exogenous morphine.

Catechol-o-methyltransferase polymorphisms predict opioid consumption in postoperative pain.

BACKGROUND:Previous studies have associated the catechol-O-methyltransferase (COMT) enzyme rs4680 polymorphism with opioid consumption in the treatment of chronic cancer pain. In this study, we evaluated the association between COMT rs4680 and rs4818 polymorphisms and opioid consumption in the acute postoperative period after a nephrectomy. METHODS:Opioid consumption and pain scores were evaluated in 152 patients for 48 hours after nephrectomy. The genotype of each patient was determined using polymerase chain reaction on DNA extracted from blood samples. The association between rs4680 and rs4818 genotypes and opioid consumption was evaluated using general linear model regression analysis. All P values and confidence intervals were Bonferroni corrected for the 3 comparisons among genotypes. RESULTS:In the 24-hour period after surgery (COMT rs4680), patients homozygous for the variant Val/Val consumed 36% (95% confidence interval, 31%–41%) more opioids than patients homozygous for the Met/Met group (P = 0.009). No statistically significant differences among the 3 genotype groups were noted for pain scores or emesis medication use in the first 24 hours after surgery. There was a statistically significant increase in emesis medication use in patients possessing the CC genotype of rs4818 when compared to patients carrying the GG genotypes (P = 0.035). In the 6- to 48-hour postsurgery period, there was significantly higher opioid consumption in the high-activity homozygotes Val/Val than in the homozygous Met/Met group for COMT rs4680 (0–6 h: P = 0.005; 0–12 h: P = 0.015; 0–24 h: P = 0.015; and 0–48 h: P = 0.023). Patients in the homozygous GG group COMT rs4818 single nucleotide polymorphism showed statistically significant differences in opioid consumption in the first 6 hours after nephrectomy compared with heterozygous CG patients (P = 0.02). CONCLUSIONS:The genetic variant of the COMT rs4680 single nucleotide polymorphism is associated with variability in opioid consumption in postoperative nephrectomy patients. The COMT rs4818 polymorphism may prove useful in predicting emesis medication use postoperatively.

Single-Nucleotide Polymorphism C3435T in the ABCB1 Gene is Associated with Opioid Consumption in Postoperative Pain

BACKGROUNDnABCB1 is a major determinant of opioid bioavailability; however, no previous studies have provided positive evidence of an association between single-nucleotide polymorphisms (SNPs) of ABCB1 and opioid usage in acute pain management. The aim of this study was to test the association between the functional SNP C3435T in ABCB1 and opioid consumption in postoperative pain in patients undergoing a nephrectomy. Additionally, we explored the association between C3435T and opioid side effect.nnnMETHODSnC3435T was genotyped in 152 patients undergoing a nephrectomy. Opioid consumption and pain scores were evaluated as well. The effect of genotype on opioid consumption was modeled using a general linear mixed model.nnnRESULTnBased on a mixed linear model, the ABCB1 three genotypes showed a statistically significant effect on opioid consumption (Fu2009=u20094.20, Pu2009=u20090.017). There was a statistically significant difference in opioid consumption among the ABCB1 three genotypes in the 0-6 hours (Pu2009=u20090.031, 95% confidence interval [CI] CC 14.7-24.8u2009mg and TT 5.2-14.6u2009mg) and 6-12 hours (Pu2009=u20090.009, 95% CI CC 5.6-13.8u2009mg and TT 1.2u2009mg-5.1u2009mg) postoperative period. There were no significant statistical differences in opioid consumption among the ABCB1 three genotypes in the 12-24 hours (Pu2009=u20090.302) and 24-48 hours (Pu2009=u20090.763) postoperative period. The TT genotype had significantly lower levels of cumulative opioid consumption compared with the CC genotype in first 24 hours after surgery (Pu2009=u20090.029). No statistically significant differences among the three genotype groups were noted for postoperative pain scores or emesis medication use in the first 24 hours after surgery.nnnCONCLUSIONnOur results demonstrate an association between the ABCB1 polymorphism (C3435T) and interindividual variations in opioid consumption in the acute postoperative period after nephrectomy. The ABCB1 polymorphism may serve as an important factor to guide acute pain therapy in postoperative patients.

Opioid-induced Hallucinations: A Review of the Literature, Pathophysiology, Diagnosis, and Treatment

Despite their association with multiple adverse effects, opioid prescription continues to increase. Opioid-induced hallucination is an uncommon yet significant adverse effect of opioid treatment. The practitioner may encounter patient reluctance to volunteer the occurrence of this phenomenon because of fears of being judged mentally unsound. The majority of the literature concerning opioid-induced hallucinations arises from treatment during end-of-life care and cancer pain. Because the rate of opioid prescriptions continues to increase in the population, the rate of opioid-associated hallucinations may also conceivably increase. With a forecasted increase in the patient-to-physician ratio, opioid therapy is predicted to be provided by practitioners of varying backgrounds and medical specialties. Hence, knowledge of the pharmacology and potential adverse effects of these agents is required. This review seeks to increase awareness of this potential complication through a discussion of the literature, potential mechanisms of action, diagnosis, and treatment strategies.

Desmoid Tumors: A Review of the Literature and Pharmacologic Management

ABSTRACT Desmoid tumors represent a nonmalignant proliferation of fibroblast-related cells. These rare tumors are difficult to treat and often persist as indolent, lifelong conditions. There are a number of treatments available for both anatomic and symptom regression. Some of these treatments, unfortunately, may not provide long-lasting results and may result in further complications. Pain is a distressing symptom that may be due to the tumor itself or the result of utilized treatments. Pharmacologic therapies represent a noninvasive alternative to surgical resection. Pain symptoms require therapeutic regimens that must be modified as the tumor evolves in expression. The individualized pain treatment program utilized may often reflect principles used in both nonmalignant and malignant pain management models. This review seeks to increase awareness of desmoid tumors through a review of the literature and discussion of its pharmacotherapeutic management.