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

https://doi.org/10.1016/S0376-8716(02)00321-6Get rights and content

Abstract

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.

Introduction

In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) recommended that Ultram®, containing a novel analgesic (tramadol hydrochloride) thought to act as a typical Mu-opioid agonist and with some analgesic activity mediated by non-opioid mechanisms (i.e. norepinephrine and serotonin reuptake inhibition (Raffa et al., 1992), be marketed without scheduling under the Controlled Substances Act (CSA). This decision was based primarily on, first, extensive pre-clinical and clinical evidence predicted a very low level abuse; and second, in 17 years on the market in Europe, abuse and dependence rates were very low. The DAAC was concerned, however, that unexpectedly high rates of abuse/dependence might emerge in this country. In response to this concern, the DAAC endorsed a recommendation that Ortho-McNeil Pharmaceuticals (OMP), the sponsor of Ultram®, establish an independent steering committee (ISC) to oversee a post-marketing surveillance program. The charge of the ISC was to develop mechanisms to proactively monitor for abuse/dependence as a means of providing an early warning signal that the drug might be found to have a higher rate of abuse and dependence in the American market than was expected. In an unprecedented step the company (OMP) agreed that, should the abuse of Ultram® be higher than expected, the ISC would simultaneously notify the FDA and OMP that Ultram® needed to be scheduled. The multi-faceted post-marketing surveillance program created by the ISC has been presented in detail in a prior publication; the rates of abuse and dependence from the launch of Ultram® in April of 1995 through June 30, 1998 were also presented (Cicero et al., 1999).

The ISC developed a two-tiered approach to detect whether Ultram® had unexpectedly high abuse potential. The first tier consisted of two phase IV post-marketing studies focusing on the potential abuse of Ultram® in pain patients and impaired health care professionals. The second tier consisted of a comprehensive, proactive surveillance program devised to detect any signal that abuse of Ultram® might be emerging. With respect to the latter, the ISC recognized that no systematic monitoring for abuse liability had ever been conducted for any newly approved psychoactive medication and thus, the surveillance program for Ultram® was unprecedented (Brewer and Colditz, 1999, Temple, 1999). The committee concluded that any surveillance program needed to incorporate the following critical elements: first, the program needed to be proactive and timely in soliciting evidence of Ultram® abuse; second, it had to be sensitive enough to detect isolated, regional clusters of abuse; third, methods needed to be developed to characterize the abuse permitting the development of intervention strategies; fourth, suspected cases of abuse needed to be validated utilizing scientifically appropriate diagnostic criteria; and finally, the program had to incorporate methods to estimate the number of patients exposed to Ultram® and hence, the rate of abuse to enable a risk-benefit analysis (i.e., cases of abuse per 100 000 patients exposed). While any adverse event, such as abuse or physical dependence is unfortunate, this risk must be balanced against the potential benefits of the drug; the rate of abuse provides such a measure.

The ISC recognized that the MedWatch system utilized by the FDA (Kessler, 1993) had a number of limitations as a proactive surveillance technique (Faich, 1986, Piazza-Hepp and Kennedy, 1995). First, the program significantly underestimates abuse since it relies upon spontaneous reports; second, the reports generally lack sufficient information for valid clinical assessments; and finally, the program primarily records events occurring in patients in whom abuse is expected to be very low and hence, probably understates the nature and scope of abuse. As a result of these limitations, the ISC developed a large national base of ‘key informants’ to proactively seek evidence of abuse in individuals at risk for abuse. The term ‘key informants’, which is borrowed from the fields of social and cultural anthropology (Agar, 1980), refers to clinicians, epidemiologists, treatment counselors, and other observers who are well recognized experts in the field of substance abuse and who are in a position to know about new and emerging drug problems in their areas. The informants provided information to the ISC at least quarterly, and each case was evaluated using the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV) criteria to determine whether abuse actually occurred. This comprehensive surveillance system (Cicero et al., 1999) provided proactive and timely information on abuse patterns stratified by postal zip codes across the country.

In earlier work, we have described in full the implementation of the surveillance program (Cicero et al., 1999) and presented the abuse rates and profiles of Ultram® during the first 3 years of marketing in the United States. In the present paper, we describe the characteristics and incidence of the withdrawal syndrome induced by abrupt cessation of chronic Ultram® use. In the course of the surveillance project, we received reports of withdrawal following abrupt discontinuation of Ultram® or, in some instances, following dose reductions in an established regimen of administration. Although the Ultram® label clearly warns of withdrawal upon abrupt discontinuation of chronic dosing, many physicians apparently did not heed this warning and abruptly stopped Ultram® therapy instead of tapering the dose as recommended. The withdrawal symptoms, in most cases, consisted of classical opioid withdrawal, as described in DSM-IV. In some cases, however, classical opioid withdrawal symptoms 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. The characteristics of the withdrawal syndrome—typical and atypical—for the 5-year period from the date of launch of Ultram® (April 1995 to March 2000) are presented in this paper.

Section snippets

IRB approval of the protocols

The Institutional Review Board (IRB) at Washington University approved the studies described in this paper; Washington University was used as the primary site for the research since the chairman of the ISC (Theodore J. Cicero) was the PI for the grant and handled all aspects of mailing the questionnaires, securing additional information as needed and distilling the data.

Detailed methods

The ISC received reports of withdrawal from two sources. First, reports of suspected withdrawal and abuse generated by Ultram®

Characteristics of Ultram® withdrawal

Table 2 shows the signs and symptoms of typical (N=367) and atypical (N=55) withdrawal from Ultram® (total=422). The incidence of specific atypical withdrawal symptoms occurring in patients diagnosed with atypical withdrawal is given as a percent of total atypical cases showing the respective symptoms. According to DSM-IV criteria at least three of the symptoms of typical opioid withdrawal listed in this table were necessary for a classification of typical opioid withdrawal or physical

Discussion

The results of these studies indicate that physicians and other healthcare professionals need to be aware of the potential for chronic Ultram® use to induce withdrawal of the classical opioid type upon abrupt cessation and sometimes even when the dose was tapered as recommended on the label. However, our results also clearly show that 1 in 8 Ultram® withdrawal cases presented as a mixture of classical opioid withdrawal with unusual features such as intense anxiety, depersonalization, delusions,

Acknowledgements

This paper is supported by a grant to Theodore J. Cicero from Ortho-McNeil Pharmaceuticals, Raritan, NJ.

References (17)

There are more references available in the full text version of this article.

Cited by (105)

  • Temporomandibular Joint Surgery

    2023, Journal of Oral and Maxillofacial Surgery
  • Medical Treatment of Disorders of Ejaculation

    2022, Urologic Clinics of North America
  • The neuropsychophysiology of tingling

    2018, Consciousness and Cognition
    Citation Excerpt :

    It is conceivable that tingling evoked by these factors is due to increased sensory processes either from peripheral tissues or spinal sensory neurons (Hess, 2001), or cerebral somatosensory areas through the ascending reward system (Boecker et al., 2008). However, drugs may also cause tingling through central processes; for example, withdrawal in addiction is also characterized by tingling (Fagerstrom & Schneider, 1989; Giakas & Davis, 1997; Hirschman, 1992; Malhotra & Bhola, 2014; Merry & Zachariadis, 1962; Senay et al., 2003). We have shown that tingling reported in various emotional and hedonic states might be caused by changes in peripheral tissues that result in activation of afferent nerves.

  • Dual Disorder Heroin Addicts: Clinical and Therapeutical Aspects

    2023, Dual Disorder Heroin Addicts: Clinical and Therapeutical Aspects
View all citing articles on Scopus
View full text