High Doses Of Tramadol Research Articles

Buprenorphine for High-dose Tramadol Dependence: A Case Report of Successful Outpatient Treatment.

Buprenorphine for High-dose Tramadol Dependence: A Case Report of Successful Outpatient Treatment.

Role of apoptosis and autophagy in mediating tramadol-induced neurodegeneration in the rat hippocampus.

Tramadol (TRA) is an analgesic prescribed for treating mild to moderate pains, the abuse of which has increased in recent years. Chronic tramadol consumption produces neurotoxicity, although the mechanisms are unclear. The present study investigated the involvement of apoptosis and autophagy signaling pathways and the mitochondrial system in TRA-induced neurotoxicity. Sixty adult male Wistar rats were divided into five groups that received standard saline or TRA in doses of 25, 50, 75, 100, or 150mg/kg intraperitoneally for 21 days. On the 22nd day, the Open Field Test (OFT) was conducted. Jun N-Terminal Kinase (JNK), B-cell lymphoma-2 (Bcl-2), Beclin1, and Bcl-2-like protein 4 (Bax) proteins and tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were measured in rat hippocampal tissue. TRA at doses 75, 100, and 150mg/kg caused locomotor dysfunction in rats and increased total and phosphorylated forms of JNK and Beclin-1, Bax, and Caspase-3. TRA at the three higher doses also increased the phosphorylated (inactive) form of Bcl-2 level while decreasing the unphosphorylated (active) form of Bcl-2. Similarly, the protein levels of TNF-α and IL-1β were increased dose-dependently. The mitochondrial respiratory chain enzymes were reduced at the three higher doses of TRA. TRA activated apoptosis and autophagy via modulation of TNF-α or IL-1β/JNK/Bcl-2/Beclin1 and Bcl-2/Bax signaling pathways and dysfunction of mitochondrial respiratory chain enzymes.

Comparative Study of Opioid Initiation With Tramadol, Short-acting Hydrocodone, or Short-acting Oxycodone on Opioid-related Adverse Outcomes Among Chronic Noncancer Pain Patients.

To compare the safety profiles of low and high-dose tramadol, short-acting hydrocodone, and short-acting oxycodone therapies among chronic noncancer pain individuals. A retrospective cohort study of individuals with back/neck pain/osteoarthritis with an initial opioid prescription for tramadol, hydrocodone, or oxycodone was conducted using IQVIA PharMetrics Plus claims for Academics database (2006 to 2020). Two cohorts were created for separately studying opioid-related adverse events (overdoses, accidents, self-inflicted injuries, and violence-related injuries) and substance use disorders (opioid and nonopioid). Patients were followed from the index date until an outcome event, end of enrollment, or data end. Time-varying exposure groups were constructed and Cox regression models were estimated. A total of 1,062,167 (tramadol [16.5%], hydrocodone [61.1%], and oxycodone [22.4%]) and 986,809 (tramadol [16.5%], hydrocodone [61.3%], and oxycodone [22.2%]) individuals were in the adverse event and substance use disorder cohorts. All high-dose groups had elevated risk of nearly all outcomes, compared with low-dose hydrocodone. Compared with low-dose hydrocodone, low-dose oxycodone was associated with a higher risk of opioid overdose (hazard ratio: 1.79 [1.37 to 2.33]). No difference in risk was observed between low-dose tramadol and low-dose hydrocodone (hazard ratio: 0.85 [0.64 to 1.13]). Low-dose oxycodone had higher risks of an opioid use disorder, and low-dose tramadol had a lower risk of accidents, self-inflicted injuries, and opioid use disorder compared with low-dose hydrocodone. Low-dose oxycodone had a higher risk of opioid-related adverse outcomes compared with low-dose tramadol and hydrocodone. This should be interpreted in conjunction with the benefits of pain control and functioning associated with oxycodone use in future research.

Buprenorphine for High-dose Tramadol Dependence: A Case Report of Successful Outpatient Treatment.

IntroductionDuring the coronavirus disease 2019 pandemic caused by the severe acute respiratory syndrome coronavirus 2, deaths from opiate drug overdoses reached their highest recorded annual levels in 2020. Medication-assisted treatment for opiate use disorder has demonstrated efficacy in reducing opiate overdoses and all-cause mortality and improving multiple other patient-centered outcomes. Treatment of tramadol dependence in particular poses unique challenges due to its combined action as opioid agonist and serotonin-norepinephrine reuptake inhibitor. Tramadol puts patients with dependence at risk for atypical withdrawal syndromes when attempting to reduce use. Little evidence is available to guide treatment of tramadol dependence.Case ReportWe present a case of high-dose tramadol addiction that began with misuse of medically prescribed tramadol for treatment of musculoskeletal back pain. The patient’s use reached oral consumption of 5000–6000 milligrams of illicit tramadol daily. She complained of common complications of tramadol use disorder including memory impairment, excessive sedation, and tramadol-induced seizures. The patient was referred to the emergency department in a withdrawal crisis seeking treatment where she was successfully managed with buprenorphine and phenobarbital and then linked to ongoing outpatient treatment.ConclusionOur report adds to the limited guidance currently available on the acute management of tramadol withdrawal and treatment of tramadol use disorder. Our case suggests the initiation of high-dose buprenorphine may be an effective and feasible option for emergency clinicians.

Abuse and misuse of tramadol among the youth in hodan district mogadishu somalia

Objectives: Tramadol is a synthetic (man-made) pain reliever (analgesic). Researchers and doctors do not know the exact mechanism of action of tramadol, but it is similar to morphine. The objective of the study was is to assess the knowledge and contact traces of tramadol in Hodan district Mogadishu Somalia. A descriptive cross-sectional survey was adopted using structured questionnaire as the major instrument for the collection of data- this was both closed and open-ended. Methodology: A sample size of 130 respondents was used through the use of simple random sampling technique. Quantitative data analysis methods were used with the aid of Statistical Package for Social Sciences (SPSS) version 21.0 in the analysis of the data. Results: The study found that majority (70%) of respondents knew about tramadol of which more happened to be males. The study found that participants take higher doses of tramadol. The study found that preponderance (58.5%) of respondents knew people who use tramadol of which majority were their friends and co-workers. It also turned out that (83.1%) of the respondents knew where tramadol is readily available. Conclusions: In determining the main purpose of tramadol as energy booster, (30%) attested sexual ecstasy and performance. In conclusion, the availability of tramadol in our Somali community should be highly regulated since its abuse among the youth is on the ascendency. It is a real issue that should be tackled with concerted effort to curtail this menace most especially in the Hodan district.

The effects of cytochrome P450 2D6 inhibitors on a high-dose tramadol taper for medically supervised opioid withdrawal: a retrospective chart review

Background: Tramadol is used off-label for medically supervised opioid withdrawal. Tramadol is metabolized by CYP2D6 to an active metabolite with significantly more pharmacologic activity compared to the parent compound.Objectives: The objective of this study is to evaluate the effects of CYP2D6 inhibitors on patient response to a tramadol taper for medically supervised opioid withdrawal.Methods: A retrospective chart review of patients who received a tramadol taper for medically supervised opioid withdrawal was conducted comparing patients who received concomitant moderate-to-strong CYP2D6 inhibitors to patients without concomitant therapy. The primary outcome was the change in Clinical Institute Narcotic Assessment (CINA) scores from baseline to discharge. Secondary outcomes included area under the curve of CINA scores over time, additional CINA outcomes, length of stay, and readmissions.Results: Of 100 charts reviewed, 30 patients received a concomitant moderate-to-strong CYP2D6 inhibitor. There were no statistically significant differences between the baseline demographics of the two groups. Change from baseline CINA to discharge did not differ significantly between the Non-2D6 group and the 2D6 group (-4.0 ± 3.83 and −4.5 ± 4.48 respectively; p = 0.606). The average CINA score for nausea and vomiting was significantly higher in the Non-2D6 group compared to the 2D6 group (0.34 ± 0.35 and 0.18 ± 0.33 respectively; p = 0.019). Otherwise there were no significant differences found in any secondary outcomes.Conclusions: Based on these results, moderate-to-strong CYP2D6 inhibitors do not appear to have a significant impact on the withdrawal course for patients treated with a high-dose tramadol taper.

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.

Impact of Chronic Tramadol Intake on Reproductive Hormones and Related Histopathological Changes in Adult Albino Rats

Background: Tramadol is a synthetic opioid analgesic, widely used in the treatment of osteoarthritis, back pain, sports injuries, and other musculo-skeletal conditions, rheumatological conditions, and headaches. Tramadol is a common prescription pain reliever as it is considered to possess a much better safety profile than other opioid analgesics. Aim of the Work: To examine the influence of chronic use of tramadol on reproductive hormones, and to outline the histopathological changes in ovaries, testes and pituitary glands of adult albino rats.Materials and Methods: A number of 90 male and female adult albino rats were used for this study. They were divided into three groups each comprising 30 rats (15 males and 15 females). Group one was the control group which received normal saline, group two was treated with low dose of tramadol (40 mg/kg) daily, while group three was treated with high dose of tramadol (80 mg/kg) daily for one month. Results: The present study revealed that there was a statistical significant decrease in serum LH, FSH, Estradiol among tramadol treated male and female groups when compared with control group. In addition, there was a significant decrease in serum testosterone level among tramadol treated male groups when compared to the control group. Furthermore, serum progesterone level showed a statistically significant decrease among the high dose tramadol treated female group when compared to both the low dose tramadol treated group and the control group but there was a statistically significant increase when comparing the low dose to the control group and the high dose group. While monitoring the effect of tramadol on serum prolactin level there was significant increase among tramadol treated male groups, while there was non significant change among tramadol treated female groups. By histopathological examination of ovaries and testes under light microscopy and pituitary glands by electron microscopy there were changes related to the hormonal changes. Conclusion: Chronic use of tramadol in rats even with its therapeutic doses has a passive effect on gonadal function affecting both males and females.

Comparison of meperidine, tramadol and fentanyl for post-spinal shivering prevention during cesarean delivery: A double-blind randomized controlled trial.

To assess the effects of intravenously administered meperidine, fentanyl and tramadol in reducing the incidence, onset time and severity of the shivering response in parturients during cesarean delivery under spinal anesthesia. Secondary outcomes included patient satisfaction and sedation scores. After Ethics board approval and informed written consent, 350 parturients (ASA physical status I or II), between 20 and 40 years of age, undergoing emergency or elective cesarean delivery under spinal anesthesia were recruited. Parturients were then randomly allocated to seven study groups: normal saline (control), low-dose meperidine (0.5 mg/kg), high-dose meperidine (0.75 mg/kg), low-dose fentanyl (0.5 mcg/kg), high-dose fentanyl (0.75 mcg/kg), low-dose tramadol (0.5 mg/kg) and high-dose tramadol (0.75 mg/kg). The incidence, onset time and severity of shivering, along with patient satisfaction and sedation scores were measured. All study drugs showed significant reduction in incidence, onset time and severity of shivering and greater satisfaction scores compared to the control group (P < 0.01). Within each drug class, no significant differences in shivering were found between the high-dose and low-dose groups. Among study drugs, low-dose tramadol was superior due to shivering prevention and significantly reduced sedation. Intravenously administered meperidine, fentanyl and tramadol reduce shivering incidence, onset time and severity in parturients undergoing cesarean delivery following spinal anesthesia. Importantly, low-dose intravenous tramadol (0.5 mg/kg) allowed shivering prevention and low sedation scores, thereby offering greater parturient satisfaction and better maternal-newborn bonding.

Low-Dose Morphine versus High-Dose Tramadol for management of moderate cancer pain: a comparative study

Low-Dose Morphine versus High-Dose Tramadol for management of moderate cancer pain: a comparative study

215 Mechanisms underlying the sexual inhibitory effect of tramadol; a study in serotonin transporter knockout rats

To investigate whether the inhibitory effects of tramadol on sexual behavior are solely due to the blockade of the serotonin (5-HT) transporter (SERT), using SERT knockout rats (SERT-/-). A crossover and randomized design was performed with 36 sexually experienced male Wistar rats (SERT+/+, SERT+/-, SERT-/-; N=12 each). Rats received acute intraperitoneal doses of 0, 5, 10, 20, 40 and 50 mg/kg tramadol hydrochloride. Furthermore, WAY100635 (5-HT1A receptor antagonist) was tested in doses 0, 0.1, 0.3 and 1 mg/kg IP and naloxone hydrochloride (μ-opioid receptor antagonist) in doses 0, 5, 10 and 20 mg/kg, IP. Finally, we tested combinations of vehicle + vehicle, vehicle + tramadol (20 mg/kg), tramadol (20mg/kg) + WAY (0.3 mg/kg), tramadol (20mg/kg) + naloxone (20mg/kg), and tramadol (20mg/kg), + WAY (0.3 mg/kg) + naloxone (20 mg/kg). Experiments were performed over several months on a 30-min sexual behavior test. In all SERT groups, intermediate and high doses of tramadol (20, 40 and 50 mg/kg) significantly decreased ejaculation, mount and intromission frequencies and at the highest dose a total inhibition effect was present. The latencies of ejaculation, mount and intromission were increased which in combination with the decreased frequencies resulted in a decreased efficiency to achieve ejaculation. WAY100635, did not affect sexual behavior in SERT+/+ animals. In accordance with previous findings, sexual behavior was inhibited in SERT-/- animals. Naloxone alone had no effect on sexual behavior, but in combination with WAY100635 or naloxone, tramadol strongly inhibited all sexual behavior parameters. The mixture of tramadol, WAY100635 and naloxone lead to complete elimination of sexual behavior in all groups.

Evaluation of analgesic and anti-inflammatory activity of a combination of tramadol-pregabalin in animal models of pain and inflammation

Background: A major goal of pain management is to provide pain relief that is clinically meaningful, sustained, and associated with minimum and reversible adverse effects. Since single analgesic drug is not effective in all patients, there is a need either to develop new and more effective drugs or to identify favourable combinations of drugs that are already available. The aim of the present was to evaluate the analgesic and anti-inflammatory activity of tramadol and pregabalin when used alone or in combination in animal models of pain and inflammation.Methods: The animals (rats and mice) were divided into eight groups with six animals in each group. Analgesia was assessed by acetic acid induced writhing and tail flick methods in mice and hot plate method in rats. Paw oedema model in rats after induction with 0.1 ml of 1% carrageenan was used to assess the anti‑inflammatory activity. The percentage inhibition of writhes and prolongation of reaction time were used for assessing analgesic activity and reduction in paw volume was used for assessing anti-inflammatory activity. The results obtained were analysed by ANOVA and Tukey HSD Post-hoc Test.Results: Treatment with tramadol pregabalin alone or in combination reduced writhing episodes significantly in acetic acid induced writhing in mice as compared to control indicating its analgesic effect and the highest percentage inhibition of pain was seen with high dose tramadol plus pregabalin. Treatment in Hot plate and Tail flick methods significantly prolonged the reaction time at all time points.Conclusions: Tramadol when combined with pregabalin may enhance its anti-nociceptive effects. If confirmed in additional models of acute and/or chronic pain this combination might be useful in the clinical management of pain not associated with inflammation.

Medical and Psychiatric Effects of Long-Term Dependence on High Dose of tramadol

Background: Tramadol dependence has been studied recently after large-scale exposure. Although tramadol dependence has increased rapidly in Egypt since 2004, no studies have evaluated the effect of high dose long-term tramadol dependence. Objectives: To address the chronic sequel of tramadol dependence over at least 5 years duration with a large dose (more than 675 mg/day, three tablets or more, each tablet of 225 mg). The study was aimed to check the physical and psychiatric status during tramadol dependence and 3 months after complete treatment. Methods: The present study was applied on 79 patients with single tramadol-dependence dose of 675 mg or more for 5 years or more. We examined the physical and psychological impact of tramadol abuse before and after 3 months of stoppage of the drug. Results: The blood chemistry was nearly within normal parameters, although slight nonsignificant rise in liver enzymes was reported in some cases. Patients during tramadol dependence period were angry, hostile, and aggressive. On the other hand, after treatment the main problem observed was the significant increase in comorbid anxiety, depressive, and obsessive-compulsive symptoms, but no increase was found in psychotic symptoms. Tramadol-dependence dose was more important than duration of use in psychiatric illness. Conclusions: Tramadol dependence on high dose could be physically safe to some limit, but psychiatrically it has many side effects.

Pain Management Discussion Forum: Serious Interaction Among Frequently Used Drugs for Chronic Pain

ABSTRACTA query and response regarding a patient who was taking high-dose tramadol and duloxetine is presented. The patient developed serotonin syndrome. Risks for this clinically important drug interaction and management of the syndrome are discussed.This report is adapted from paineurope 2013; Issue 4, ©Haymarket Medical Publications Ltd., and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, Ltd., and is distributed free of charge to health care professionals in Europe. Archival issues can be accessed via the Web site: http://www.paineurope.com, at which European health professionals can register online to receive copies of the quarterly publication.

Premedication with oral tramadol reduces severity of postoperative shivering after general anesthesia

Background:Postanesthetic shivering (PAS) is an accompanying part of general anesthesia with different unpleasant and stressful complications. Considering the importance of proper prevention of PAS in order to reduce its related adverse complications in patients undergoing surgery, in this study, we investigated the effect of orally administrated tramadol in the prevention of this common complication of general anesthesia.Materials and Methods:In this prospective randomized double-blind clinical trial, 80 ASA I and II patients aged 15-70 years, scheduled for elective surgery under general anesthesia, were randomized to intervention (oral tramadol 50 mg) and placebo groups. PAS was evaluated during surgery and in the recovery room, and compared in the two study groups.Results:PAS was seen in 5 patients (12.5%) in the intervention group and 10 patients (25%) in the placebo group (P = 0.12). The prevalence of grade III and IV shivering was 7.5% (3/40) and 25% (10/40) in tramadol and placebo groups, respectively (P = 0.03).Conclusion:The overall prevalence of PAS was not significantly different in the two study groups, but the higher grades of shivering which needed treatment were significantly lower in the tramadol group than in the placebo, and those patients who received tramadol experienced milder form of shivering. It is suggested that higher doses of tramadol would have better anti-shivering as well as analgesic effects. Studying different doses of tramadol would be helpful in this regard.

Tramadol abuse potential and resultant withdrawal seizures

Tramadol is a centrally acting atypical opioid analgesic with additional serotonin-norepinephrine reuptake-inhibiting effects used to treat moderate to moderately severe pain with propensity for abuse potential. The case of tramadol dependence discussed in this case report developed severe dependence with high doses of tramadol, used as a drug for treating his migraine. The individual learned to self-medicate with the medication. The author further emphasize on the regulation of tramadol prescription.

A patient with Tramadol dependence and predictable provoked epileptic seizures

Tramadol is an atypical, centrally acting synthetic analgesic with propensity for provoked seizures as well as abuse potential. The index case of Tramadol dependence discussed in this case report developed multiple epileptic seizures with high doses of Tramadol, used as a sexual enhancer by him, and later he learned to prevent the seizures by self-medicating with Alprazolam. The authors further emphasize on the regulation of Tramadol prescription.

Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction

We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.

Abuse liability and reinforcing efficacy of oral tramadol in humans

BackgroundTramadol, a monoaminergic reuptake inhibitor, is hepatically metabolized to an opioid agonist (M1). This atypical analgesic is generally considered to have limited abuse liability. Recent reports of its abuse have increased in the U.S., leading to more stringent regulation in some states, but not nationally. The purpose of this study was to examine the relative abuse liability and reinforcing efficacy of tramadol in comparison to a high (oxycodone) and low efficacy (codeine) opioid agonist. MethodsNine healthy, non-dependent prescription opioid abusers (6 male and 3 female) participated in this within-subject, randomized, double blind, placebo-controlled study. Participants completed 14 paired sessions (7 sample and 7 self-administration). During each sample session, an oral dose of tramadol (200 and 400mg), oxycodone (20 and 40mg), codeine (100 and 200mg) or placebo was administered, and a full array of abuse liability measures was collected. During self-administration sessions, volunteers were given the opportunity to work (via progressive ratio) for the sample dose or money. ResultsAll active doses were self-administered; placebo engendered no responding. The high doses of tramadol and oxycodone were readily self-administered (70%, 59% of available drug, respectively); lower doses and both codeine doses maintained intermediate levels of drug taking. All three drugs dose-dependently increased measures indicative of abuse liability, relative to placebo; however, the magnitude and time course of these and other pharmacodynamic effects varied qualitatively across drugs. ConclusionsThis study demonstrates that, like other mu opioids, higher doses of tramadol function as reinforcers in opioid abusers, providing new empirical data for regulatory evaluation.

Pharmacodynamic profile of tramadol in humans: influence of naltrexone pretreatment

Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects. This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans. This inpatient, double-blind, randomized, within-subject study examined the effects of oral placebo, tramadol (87.5, 175, and 350 mg), and hydromorphone (4 and 16 mg; positive control) after 1 h pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 h after initial drug administration. Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of "Good Effects" and "Liking" but also increased ratings of "Bad Effects." Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol's positive subjective effects and actually enhanced several unpleasant subjective ratings. Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. High-dose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol's subjective profile of action.