Tramadol post-marketing surveillance in health care professionals

Tramadol has been marketed in the US since 1995. The US Food and Drug Administration agreed to release tramadol as a non-scheduled drug if proactive post-marketing surveillance studies would be conducted. This study was one of two phase IV protocols that were part of the overall surveillance program. It focused on impaired health professionals who are a high risk/high access population for drug abuse. All active participants in four state monitoring programs between November 1, 1995 and August 15, 1998 (n = 1,601) were recruited for the study. With the exceptions of implementing a standardized intake interview and urine testing for tramadol metabolites, all states operated their programs in the usual fashion. The programs were alerted to persistent non-prescribed tramadol use so that appropriate interventions could be employed. Despite availability of tramadol and the conditions that might lead to its abuse, the incidence rate for tramadol use in the study population was only 69 per thousand persons per year and the incidence rate for tramadol abuse or dependence was 6.9 per thousand persons per year.     

The Diversion of Ultram, Ultracet, and generic tramadol HCL

Ultram (tramadol HCL) was approved by the Food and Drug Administration in 1994 as a non-scheduled drug under the Controlled Substance Act. The non-scheduled status was contingent on the development and implementation of a comprehensive post-marketing surveillance program by an Independent Steering Committee external to Ortho-McNeil Pharmaceutical charged with monitoring abuse and recommending scheduling if unexpectedly high abuse occurred. The program developed by this committee was composed of a variety of studies, and the results of the first three years of the surveillance efforts revealed that the rate of Ultram abuse was low. At a meeting of the FDA in 1998 to reexamine the scheduling status of Ultram, it was recommended that the scope of the postmarketing surveillance program be broadened to include data on diversion. After a 1-year pilot study, by January 2002, a nationwide diversion survey was fully operational. This brief communication describes the experiences of this diversion study, and compares the findings on the diversion of Ultram and other tramadol HCL products with that of more widely abused drugs. Survey data suggest that the diversion of Ultram and other tramadol products is low, and overall, diversion investigators did not consider tramadol to be a problem in their respective jurisdictions.     

Rates of abuse of tramadol remain unchanged with the introduction of new branded and generic products: results of an abuse monitoring system, 1994-2004

PURPOSE: The analgesic Tramadol HCl (Ultram) was approved in 1994 as a non-scheduled drug under the CSA provided that a novel risk-management program would be developed by an Independent Steering Committee (ISC). The risk-management program began in 1995 with the launch of Ultram, and has been modified over the past decade to accommodate Ultracet (Ultram and acetaminophen) in 2001 and generic tramadol in 2002. This provided a unique opportunity to study the potential changes in abuse as the generic and combination products became available. METHODS: To proactively detect cases of abuse and diversion, the ISC developed a comprehensive questionnaire which was completed quarterly by an extensive network of drug abuse experts (n = 309) and police agencies (n = 100) who were asked to indicate how many diversion cases involving Ultram, Ultracet, and generic tramadol were identified during the preceding 3 months and what were the ten most commonly diverted drugs in their catchment area during that period. RESULTS AND CONCLUSIONS: The data generated demonstrate that the abuse of tramadol remained very low despite new branded and generic formulations. Contrary to the hypothesis that cheaper generic drugs would lead to higher rates of abuse, we found no increase in abuse with the introduction of generic tramadol. Ultracet abuse rates, unlike those found with other widely used hydrocodone and oxycodone combination products, have been even lower than that observed for tramadol. Since the FDA has now mandated that proactive risk-management plans be implemented for new drugs, the tramadol risk-management plan may be useful as a prototypic model which can be modified to accommodate other drugs with abuse potential.     

An independent assessment of MEDWatch reporting for abuse/dependence and withdrawal from Ultram (tramadol hydrochloride)

OBJECTIVE: Assess the validity of medical products reporting program (MEDWatch) reports of abuse/dependence and withdrawal associated with Ultram (tramadol). METHODS: Reports of possible abuse/dependence or withdrawal associated with Ultram during 13 quarters following launch were spontaneously reported to the manufacturer Ortho-McNeil Pharmaceutical (OMP) and also solicited from 255 NIDA grantees and addiction treatment professionals by an Independent Steering Committee (ISC). Reports were classified by the ISC using DSM-IV criteria, by the Drug Safety and Surveillance (DSS) units of Robert Wood Johnson Pharmaceutical Research Institute (PRI) using World Health Organization Adverse Reaction Terms (WHOART) terms, and reported to the food and drug administration (FDA) via MEDWatch. Rates of abuse/dependence and withdrawal per 100000 persons exposed were calculated separately for classifications made by the PRI and the ISC, and confidence intervals calculated to determine the degree to which they agreed. RESULTS: For 681 reports submitted to PRI, confidence intervals of ISC ratings contained PRI ratings 12 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. For 242 reports submitted to the ISC, confidence intervals of ISC ratings contained PRI ratings 10 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. Proactive surveillance increased the total number of cases of abuse/dependence but not withdrawal. Many cases of withdrawal without signs or symptoms of abuse/dependence were identified. CONCLUSIONS: There was good/excellent concordance between MEDWatch and ISC classifications. Proactive surveillance increased cases of abuse/dependence but not withdrawal. Withdrawal with no signs or symptoms of dependence was common. More use of proactive surveillance is likely to improve assessments of public health risks associated with adverse events.     

Tramadol intoxication: a review of 114 cases

Tramadol as a centrally acting analgesic is extensively used in the management of moderate to severe pain. It slightly affects opioid receptors and inhibits the reuptake of norepinephrin and serotonin in the CNS. There are reports about toxicity and abuse of tramadol. The objective of the present study was to evaluate epidemiology of intentional tramadol intoxications. All poisoning cases that admitted to Loghman-Hakim Hospital Poison Center from April to May 2007 were studied. A total of 114 cases (82 men and 32 women) of intentional tramadol intoxications with the median age of 23.66 +/- 6.87 years (range 16-54 years) were identified. Other illicit drugs were found to be used in combination with tramadol in some of the cases, which among them benzodiazepines were the most common. Tramadol overdose has been one of the most frequent causes of drug poisoning in the country in the recent years, especially in male young adults with history of substance abuse and mental disorders. Nausea, vomiting, Central Nervous System (CNS) depression, tachycardia, and seizure are the most common findings in this kind of poisoning. Cardiopulmonary arrest was found as the cause of death in cases who had ingested more than 5000 mg tramadol.     

Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur

In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concluded that Ultram (tramadol hydrochloride) could be marketed as an analgesic drug without scheduling under the Controlled Substances Act based upon extensive pre-clinical, clinical and European epidemiological data. However, to guard against unexpectedly high levels of abuse in the United States, the DAAC recommended that an independent steering committee (ISC) be appointed to proactively monitor abuse/dependence. In the event that high rates of abuse were found, this ISC was given the authority to immediately recommend to the FDA that Ultram be scheduled. In the course of the surveillance project, the ISC received reports of withdrawal following abrupt discontinuation of Ultram and in some instances, following dose reductions. In most cases, the withdrawal symptoms consisted of classical opioid withdrawal, but in some cases were accompanied by withdrawal symptoms not normally observed in opiate withdrawal, such as hallucinations, paranoia, extreme anxiety, panic attacks, confusion and unusual sensory experiences such as numbness and tingling in one or more extremities. Withdrawal symptoms of either type were one of the more prevalent adverse events associated with chronic Ultram use, comprising nearly 40% of all adverse events reported with Ultram. Most of these consisted of typical opiate withdrawal symptoms, but 1 in 8 cases presented as atypical. These results indicate that physicians and other healthcare professionals need to be aware of the potential of Ultram to induce withdrawal of the classical opioid type, and that atypical withdrawal may also occur.     

Development and application of a system for monitoring drug abuse: the Malaysian experience

Monitoring systems are useful epidemiological instruments for assessing the problem of drug abuse. The rapid growth of the drug dependence problem in Malaysia led to increased awareness of the need for a system for continuous monitoring of the situation. Preliminary work on the design of an appropriate monitoring system was initiated in 1976. A fully integrated national reporting system was established in 1978, linking all public services and agencies coming into contact with drug-dependent persons, including law enforcement agencies, drug abuse treatment and rehabilitation centres, and social and welfare institutions. The information system included a mechanism for systematic gathering, processing, analysing and presenting essential data on the prevention, control and management of drug abuse problems. It also included reporting on drug-related events, such as hospitalizations and arrests, as well as data on known drug-dependent persons and new cases of dependence. The system has been used for routine monitoring of the extent, trends, patterns and other characteristics of drug abuse problems in Malaysia, providing basic information for policy-making and programme planning. On the basis of data generated by the system, it was estimated that the prevalence rate of drug-dependent persons per 100,000 population increased from 84.3 in 1976 to 754.6 in 1986. It was estimated that there were 119,001 drug-dependent persons in Malaysia in 1986.     

A team approach to adverse drug reaction surveillance: success at a tertiary care hospital

A retrospective adverse drug reaction (ADR) reporting system has been in place at Cedars-Sinai Medical Center for 7 years. Initially, the system identified 300 to 400 ADRs per year. After adding a checklist, that number increased to 750 to 850 per year, an ADR rate of about 2% of total patient admissions. To increase the ADR reporting rate, we initiated a concurrent surveillance program in conjunction with the retrospective system. In the first year of the program, the combined systems identified 1,174 ADRs. In addition, the ADR rate per 100 patient days increased to between 0.5 and 0.7, and the ADR per admission rate increased to 4%. As a result of the more effective ADR surveillance program, the P & T Committee has additional data from which to develop guidelines and educational programs to increase ADR awareness and prevention, and thus, to improve patient outcomes.     

Flunitrazepam a benzodiazepine most used among drug abusers

Flunitrazepam (FZ) is a sedative/hypnotic nitro-benzodiazepine. This drug has been accepted by both patients and physicians and in the last 20 years flunitrazepam has been included and studied in many clinical trials so, in many countries, flunitrazepam is one of the most prescribed hypnotic. Since 1980 it has been found that FZ began to be a popular drug among drug abusers all over the word. However, little is known about the difference between Fz and other Benzodiazepines in capacity to produce physiologic dependence or in ability to produce drug taking or drug seeking behaviour. Flunitrazepam has little risk of abuse by the vast majority of patients; however when the drug is taken i. v. or intranasally, its effect is much faster and risk of abuse is much greater. In this report we examine the reasons why some populations of drug abusers prefer flunitrazepam over the other benzodiazepines.     

Dependence Potential of Tramadol: Behavioral Pharmacology in Rodents

Tramadol is an opioid analgesic agent that has been the subject of a series of case reports suggesting potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive in Korea. In this study, we examined the dependence potential and abuse liability of tramadol as well as its effect on the dopaminergic and serotonergic systems in rodents. In animal behavioral tests, tramadol did not show any positive effects on the experimental animals in climbing, jumping, and head twitch tests. However, in the conditioned place preference and self-administration tests, the experimental animals showed significant positive responses. Taken together, tramadol affected the neurological systems related to abuse liability and has the potential to lead psychological dependence.     

The Swedish methadone maintenance program: A controlled study

Thirty-four drug addicts, aged 20–24 years, with a history of 4–8 years of intravenous heroin abuse, were randomly assigned either to a methadone maintenance treatment (MMT) (17) or to an untreated group (17). The untreated controls could not apply for entrance to the program until two years later.It was found that after two years 12 MMT patients had abandoned their drug habits and begun work, whereas 5 had recurrent drug abuse problems. Of the controls, one was drug-free and gainfully employed, 12 were continuously abusing heroin (3 of these had incurred potentially fatal diseases in consequence), 2 were in prison and 2 had died. Two to seven years after their first visit to the Psychiatric Research Center 8 of the original control group have been accepted into the program. At present 19 (out of 25 admitted) are gainfully employed and no longer abusing drugs. Among the remaining controls 4 are dead, 3 are in prison, one in spite of a serious heart condition abuses heroin and one is drug-free.The rehabilitation rate was thus 76 per cent in the program as compared to 6 per cent among the control group. In addition, MMT obviously reduced the high morbidity and mortality rates found in a selection of heroin addicts who fulfilled the admittance criteria of the Swedish program.     

The changing epidemiology of severe cytomegalovirus disease in Australia

Few studies have reported the epidemiological characteristics and burden of severe cytomegalovirus (CMV) in the hospital setting. This study used data compiled by the Australian Institute of Health and Wealthfare(1) to examine the trends in hospital admissions due to CMV in different patient groups. As CMV disease mainly occurs in high-risk populations and almost always results in hospitalization, hospital data are an appropriate source of information on the epidemiology of clinically relevant disease. The study found that between 1993 and 2001 the average annual rate of hospital admissions where CMV was identified as the principal reason for admission amounted to 14.2 cases per 100,000 populations. This rate varied between 21.6 (1993/94) and 2.0 (2000/01) per 100,000 per year, and was always somewhat higher for men compared to women. The average annual incidence of children admitted to hospital with congenital CMV (principal and secondary diagnosis) in children aged 0-4, 5-9 and 10-14 years was 1.4, 1.3 and 0.4 per 100,000 respectively. Correlations with Human Immunodeficiency Virus (HIV), organ transplantation and other causes of immuno-suppression were also examined. The burden of severe CMV disease in Australia was found to be significant and comparable to other diseases for which national vaccination programs exist. As new vaccines for CMV may soon be available, understanding the pre-vaccination burden of CMV disease is useful for planning a vaccination program should a suitable vaccine be developed.     

Tramadol acts as a weak reinforcer in the rat self-administration model, consistent with its low abuse liability in humans

Rodent models of abuse potential are considered to represent a false positive with respect to the low risk of abuse liability associated with the atypical opioid analgesic tramadol. This may reflect either the predictive limitations of the models used to formulate this proposition (drug discrimination and conditioned place preference) or the predictive ability of the rodent per se. To address this concern, we used the rat self-administration model to examine the reinforcing properties of tramadol (0.3-3 mg/kg/infusion) under fixed (FR) and progressive-ratio (PR) schedules of reinforcement. Comparisons were made with the typical opioid analgesics morphine (0.03-0.3 mg/kg/infusion) and remifentanil (0.001-0.03 mg/kg/infusion). All three compounds maintained responding under an FR3 schedule of reinforcement, although clear differences were observed in the rates of responding between compounds. Under a PR schedule, morphine and remifentanil maintained comparable break points, while break points for tramadol did not differ from vehicle. Thus, when examined in the self-administration model, tramadol acts as a relatively weak reinforcer in rodents. These data are consistent with the low risk of tramadol abuse liability in humans and highlight the value of using multiple abuse potential models for assessing abuse liability.     

Methadone detoxification of tramadol dependence

Tramadol hydrochloride is a centrally acting analgesic with a partial affinity for the opiate receptor (mu), having an analgesic potency estimated to be one tenth that of morphine. While preclinical investigations suggested that abuse liability associated with tramadol use is low, there are increasing numbers of cases reported to the U.S. Food and Drug Administration of abuse, dependence, and withdrawal associated with tramadol use. A case of a patient with tramadol dependence requiring detoxification with methadone is presented. Acute management of significant tramadol dependence has not yet been reported in the literature. Long-term treatment issues are also discussed.     

The community epidemiology work group approach

"Drug abuse" provides many unique challenges to the research community. Some of these involve fundamental epidemiologic issues, such as measuring the extent of the problem, identifying and assessing changes in patterns and trends, detecting emerging "drugs of abuse", characterizing vulnerable populations and determining health and social consequences. A number of research methods are employed to address these issues. This paper describes one of these--a model in which ongoing surveillance of "drug abuse" is maintained through a network of community-based researchers, local officials, academics, and other interested and qualified members of the community. Timely, accurate, and cost-effective data can be generated through systematic collection and analysis of indirect indicators of "drug abuse" that are often routinely produced by a variety of community sources. This information, in turn, can be used to make informed public health policy decisions. The community-based network model has been implemented at the city, state, national, regional, and international levels, and a case is made that this type of program could be useful, as well, in understanding the dynamics of "drug abuse" in rural areas of the country.     

河南省医用麻醉、精神药物滥用情况分析

目的了解河南省2005～2009年监测报告中医用麻醉、精神药物滥用的流行现况和行为特征,为加强特殊药品管理以及本地区政府相关部门制定防治措施提供依据。方法采用国家药物滥用监测中心编制的《药物滥用监测调查表》,对2005～2009年本地区戒毒机构收戒药物滥用者进行监测,其中将医用麻醉、精神药物滥用情况作为本项研究调查内容。结果滥用的医用麻醉、精神药物种类由2005年10种增长至2009年的15种。主要滥用品种包括度冷丁、安定、吗啡、三唑仑、曲马多等,此5种药物占历年统计结果的前5位。结论滥用的医用麻醉、精神药物种类呈增长趋势,本地区滥用的医用麻醉、精神药物主要包括度冷丁、安定、吗啡、三唑仑、曲马多,同时存在其他医用麻醉、精神药物及部分处方药。