The role of α7-nicotinic acetylcholine receptor in a rat model of chronic nicotine-induced mechanical hypersensitivity.

Smokers have a higher incidence of chronic pain than non-smokers, but the neural mechanism is not yet fully understood. Nicotine is the main component of tobacco and acts as an agonist for nicotinic cholinergic receptors (nAChRs) in the nervous system. This study was approved by the IACUC of UM. The effects of chronic nicotine administration on mechanical sensitivity were studied using a rat model. The changes in the expression levels of the α7 isoform of nAChR (α7-nAChR), inflammatory cytokines TNFα and COX-2, as well as the density of neuro-immune cells (astrocytes and microglia) were measured concurrently. The results indicate that long-term nicotine administration induces hypersensitivity to mechanical stimuli, as demonstrated by a significant reduction in the pain perception threshold. In response to nicotine, the expression levels of α7-nAChR increased in the periaqueductal gray matter (PAG) and decreased in the spinal cord. Acute administration of the selective α7-nAChR agonist CDP-Choline reversed this hypersensitivity. Chronic nicotine administration led to an increase of microglial cells in the dorsal horn of the spinal cord and increased expression levels of the cytokines TNFα and COX-2. This study suggests that decreased α7-nAChR expression in the spinal cord, as a result of long-term exposure to nicotine, may be causatively linked to chronic pain. Simultaneously, the increase of neuro-immune factors in the spinal cord is also a potential factor leading to chronic pain.

Tramadol-associated hallucinations: a systematic review and narrative synthesis of their pathophysiology, diagnosis, and treatment.

BACKGROUND: Recent prescribing trends reflect government-led efforts undertaken in both the U.S. and Canada to decrease opioid use. These provisions reflect a reduction in the use of many potent opioids in favour of tramadol. Despite the purported benefits of tramadol over other opioids, little remains known about tramadol-associated hallucinations (TAH). METHODS: We conducted a systematic literature search in Embase, Medline, Cochrane CENTRAL, CINAHL, PubMed, Scopus, PAHO Virtual Health Library, MedNar, and ClinicalTrials.gov to find reported cases of hallucinations associated with the use of tramadol. For all corresponding cases reporting hallucinations secondary to tramadol use, we extracted data on patient demographics, medical management, and the details on hallucinations. Cases were categorized as "probable TAH" if the evidence supported an association between hallucinations and tramadol use, or "possible TAH" if hallucinations were attributed to tramadol use but the supporting evidence was weak. The "probable TAH" cases were further classified as "isolated TAH" if hallucinations were the primary complaint, or "other existing medical condition" if concurrent signs and symptoms alluded to a diagnosis of an existing medical condition. We then conducted a narrative synthesis of the available literature to contextualize these results. RESULTS: A total of 941 articles were identified in the initial search. No observational studies or randomized clinical trials were identified with our systematic review; only case reports were found. After a thorough screening, 34 articles comprising 101 patients reported an association between tramadol use and hallucinations. Among these 101 cases, 31 were "probable TAH" and 70 were "possible TAH". Of the 31 cases of "probable TAH", 16 cases were "isolated TAH" while the remaining 15 cases belonged to "other existing medical condition". CONCLUSIONS: Tramadol-associated hallucinations can result in auditory or visual disturbances, although multisensory symptoms have also been reported. The mechanism underlying TAH remains poorly understood and likely involves numerous receptor types. The relative risk of hallucinations from tramadol compared with other opioids remains unclear.

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.

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.

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.

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

UNLABELLED: Recent 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). METHODS: Two 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. RESULTS: It 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). CONCLUSION: This study demonstrated that female patients possessing the PM genotype of CYP2D6 and patients who smoke had a higher incidence of acute severe postoperative pain.

Tapentadol extended-release: a recent addition to our analgesic armamentarium.

SUMMARY In the never-ending process of providing therapy with diminishing side effects, pain medicine stands out as an important area of work. Ever since the introduction of opioids and elucidation of their mechanisms pharmaceutical researchers have sought a compound that provides long-term analgesia with none of the side effects that include somnolence, lethargy, tolerance, addiction, gastrointestinal symptoms and so on. This article reviews one of the latest improvements in analgesia, the formulation of tapentadol as an extended-release medication. Despite not claiming to have eliminated all the negatives of narcotics tapentadol extended-release seems to have made inroads to that goal.

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

BACKGROUND: The interleukin-1 receptor antagonist (IL-1Ra) is the principal determinant of IL-1ß bioactivity within the IL-1 gene cluster, regulating IL-1α and IL-1ß 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. METHODS: Opioid 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. RESULTS: Differences 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. CONCLUSIONS: The 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.

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?

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, micro-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 micro-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 impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption.

BACKGROUND: Endogenous 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. METHODS: After 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. RESULTS: CYP2D6 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. CONCLUSIONS: Our 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.

Coping with disaster: relocating a residency program.

In September 2005, in the aftermath of Hurricane Katrina, the Tulane University School of Medicine relocated temporarily from New Orleans to the Baylor College of Medicine in Houston, Texas. For Tulane's residency program in anesthesiology, a training consortium was formed in Texas consisting of the University of Texas at Houston, Baylor College of Medicine, the University of Texas Medical Branch at Galveston, and the M.D. Anderson Cancer Center. The authors explain the collaborative process that allowed the consortium to find spaces to accommodate Tulane's 30 anesthesiology residents within 30 days after they left New Orleans, and they offer reflections and recommendations. The residents were grateful to continue training close to home, and for maintaining the Tulane program. The consortium successfully provided an administrative and academic framework, logistical support, clinical capacity for the residents to complete the required numbers and types of cases, and integration into preexisting didactic programs. Communications represented a major challenge; the importance of having an up-to-date disaster plan, including provisions for communication using more than one modality or provider, cannot be underestimated. Other challenges included resuming a training program without basic information regarding medical credentials or training status, competing for resources with businesses that had also relocated, maintaining a coordinated decision-making process, and managing the behavioral sequelae after the disaster. Of the original 30 Tulane residents, 23 (77%) relocated to Houston. Seventeen (74%) of those who relocated either graduated or returned with the program to New Orleans. The program has retained its status of full accreditation.

Does dysregulation of catechol-O-methyltransferase predispose to opioid-induced hallucinations? A report of a patient with microdeletion of chromosome 22 and opioid-associated hallucinations.

Velocardiofacial syndrome is a genetic disorder associated with a microdeletion on the long arm of chromosome 22, and this segment is responsible for coding catechol-O-methyltransferase, an enzyme involved in dopamine degradation. We submit a case of velocardiofacial syndrome and Madelung deformity of the wrists presenting with hallucinatory phenomena associated with opioid exposure. Overactivity of the dopaminergic system has been postulated to cause schizophrenia in this population, and here we speculate that dysregulation of dopamine metabolism may have predisposed our patient to an increased risk of opioid-induced hallucinations. Further research is necessary to explore this relationship.

Dexmedetomidine and low-dose ketamine provide adequate sedation for awake fibreoptic intubation.

PURPOSE: We report the use of the alpha2 agonist, dexmedetomidine, with low-dose ketamine as a safe and effective treatment strategy to provide adequate comfort and sedation for a patient who fulfilled criteria of a difficult airway and required awake fibreoptic intubation (AFOI). CLINICAL FEATURES: A 52-yr-old male with prostate cancer presented for radical prostatectomy. He reported several failed intubations with previous surgeries and airway examination was consistent with a difficult intubation. In addition, previous fibreoptic intubations were unsuccessful. The patient reported extreme apprehension concerning his airway management. The goal of medicating patients for AFOI includes providing comfort and sedation without causing a change in ventilatory status. Dexmedetomidine has a high affinity for the alpha2 receptor and results in sedation without change in ventilatory status. In addition, dexmedetomidine is a potent anti-sialgogue which makes it desirable for cases involved with airway instrumentation. A loading dose of dexmedetomidine followed by a continuous infusion provided comfort and sedation within ten minutes. While bradycardia and hypotension have been reported with dexmedetomidine use, concurrent low-dose ketamine was employed in this case for it's cardiostimulatory properties and no bradycardia and hypotension were noted. The airway was anesthetized with selective nerve blocks and conditions for airway instrumentation were excellent. There was no change in oxygen saturation or ventilatory status during the administration of medications or airway manipulation. The patient was comfortable, sedated and tolerated the procedures well. There was no recall of the procedure. CONCLUSION: Dexmedetomidine and concurrent low-dose ketamine provided sedation and comfort to this patient who required an AFOI.

Improvement in the level of psychosocial functioning in chronic pain patients with the use of risperidone.

Psychiatric morbidity is a common complication of chronic pain. Psychopathology may lead to psychosocial dysfunction and poor prognosis for rehabilitation. Emotional factors associated with chronic pain may include depression with anxious and angry affect. Antidepressant medication is a common adjuvant pharmacological treatment in the chronic pain patient. While uncomplicated depression may respond well to antidepressants, some cases are treatment resistant. We present two cases of chronic pain patients with associated depression with angry affect that did not respond to conventional treatment. Addition of the atypical antipsychotic risperidone resulted in symptomatic improvement and higher levels of psychosocial functioning. Atypical antipsychotics may be useful in selected patients with chronic pain and treatment-resistant depression.