U.S. Department ofjustice

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1 U.S. Department ofjustice Drug Enforcement Administration Schedules of Controlled Substances: Placement of Tramadol into Schedule IV Background, Data, and Analysis: Eight Factors Determinative of Control and Findings Pursuant to 21 U.S.C. 812(b) Prepared by Office of Diversion Control, Drug and Chemical Evaluation Section Washington, D.C May 2013

2 I. Background In October and November 2005, the Drug Enforcement Administration (DEA) received four citizen petitions requesting that 21 CFR be amended so that tramadol be controlled as a scheduled substance under the Controlled Substances Act (CSA). Three ofthese petitions specifically requested the placement oftramadol in schedule III, while the remaining petition did not specify a particular level ofcontrol. Tramadol is an opioid analgesic that produces its primary opioid-like action through an active metabolite, O-desmethyltramadol, referred to below as the Ml metabolite. It was originally synthesized by Grunenthal Research Laboratories in 1962 and first marketed in West Germany for the treatment ofmoderate to moderately severe pain in In March 1995, the Food and Drug Administration (FDA) approved tramadol as a non-controlled, non-traditional, centrally acting analgesic under the trade name ULTRAM (50 mg tramadol) for marketing in the United States. Since then several other tramadol formulations were approved for marketing as immediate-release, extended release products and as generic products and extended release products. Pursuant to 21 U.S.C. 811(a) and (b), DEA gathered the available data on tramadol and in April 2007, DEA requested that the Department ofhealth and Human Services (HHS) provide a scientific and medical evaluation ofthe available information and a scheduling recommendation for tramadol, in accordance with 21 U.S.C. 811(b). On September 16, 2010, pursuant to 21 U.S.C. 811(c), the HHS provided to the DEA a scientific and medical evaluation entitled "Basis for the Recommendation to Schedule Tramadol In Schedule IV of the Controlled Substances Act" and a scheduling recommendation (HHS review, 2010). Following consideration ofthe eight factors and findings related to the substance's abuse potential, legitimate medical use, and dependence liability, HHS recommended that tramadol be controlled in schedule IV of the CSA under 21 U.S.C. 812 (b). The CSA requires DEA, as delegated by the Attorney General, to determine whether the HHS' scientific and medical evaluation and scheduling recommendation and all other relevant data constitute substantial evidence that the substance should be scheduled (21 U.S.C. 811(b)). This document contains an explanation ofthe relevant data that DEA considered. Pursuant to 21 U.S.C. 811(c), the DEA reviews the facts and all other relevant data. This document is a summarized review ofthe relevant data, law enforcement information and a determination to place tramadol into schedule IV ofthe CSA. '28 CFR0.100(b) DEA/OD/ODE Page 2 of21 May 2013

3 II. Eight Factors Determinative of Control Pursuant to 21 U.S.C. 811(c), DEA must consider eight factors in making any finding of substantial evidence ofpotential for abuse, including the data and law enforcement information relevant to. The information contained in this document is organized according to the eight factors as specified in 21 U.S.C. 811 (c). Factor 1: Tramadol's Actual or Relative Potential for Abuse The term "Abuse" is not defined in the CSA. However, the legislative history ofthe CSA suggests using the following four prongs in determining whether a particular drug or substance has a potential for abuse2: There is evidence that individuals are taking the drug or other substance in amounts sufficient to create a hazard to their health or to the safety ofother individuals or to the community; or There is significant diversion of the drug or other substance from legitimate drug channels; or Individuals are taking the drug or substance on their own initiative rather than on the basis ofmedical advice from a practitioner licensed by law to administer such drugs; or The drug is a new drug so related in its action to a drug or other substance already listed as having a potential for abuse to make it likely that the drug substance will have the same potential for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health ofthe user or to the safety ofthe community. Ofcourse, evidence of actual abuse ofa substance is indicative that a drug has a potential for abuse. The above mentioned four prongs as applied to tramadol are discussed below. In addition to the information HHS provided in their scientific and medical evaluation document for tramadol, DEA considered all other relevant data and found that: a. Individuals are taking tramadol in amounts sufficient to create a hazard to their health or to the safety ofother individuals or to the community. Published case reports, case series, and data from databases such as the Drug Abuse Warning Network (DAWN) suggest that individuals are taking tramadol in amounts sufficient to create hazard to their health, to the safety ofother individuals or to the community. Tramadol abuse is associated with serious adverse events including deaths, drug dependence, drug withdrawal symptoms, seizures, serotonin syndrome, and other serious medical problems. 2Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No , 91st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, DEA/OD/ODE Page 3 of21 May 2013

4 The Drug Abuse Warning Network (DAWN) is a Substance Abuse and Mental Health Services Administration (SAMHSA) database which collects data on drug-related emergency department (ED) visits from a nationally representative sample ofhospitals in the U.S. and a selection of metropolitan areas. HHS reviewed and analyzed DAWN data from 2004 through 2008 and found that the estimated annual nonmedical ED visits from nonmedical use oftramadol/combinations continually increased from 4,849 ED visits to 11,850 ED visits. DEA further evaluated the updated DAWN data and found that this increasing trend for tramadol continued in 2009 and 2010 (15,349 and 16,251 ED visits respectively). There was a significant increase of37% for tramadol from 2008 (11,850 visits) to 2010 (16,251 visits). However, these annual numbers for tramadol/combinations were less than those for fentanyl/combinations (Schedule II or C-II), methadone (C-II), morphine/combinations (C-II), oxycodone/combinations (C-II), hydrocodone/combinations (C-III) during this period. These numbers for tramadol/combinations were closer to the corresponding numbers for hydromorphone (C-II), buprenorphine/combinations (C- III), codeine/combinations (C-II, -III, and -V) and propoxyphene/combinations (C-IV). The American Association of Poison Control Centers (AAPCC) manages the National Poison Data System (NPDS), which is the only near real-time comprehensive poisoning surveillance database in the U.S. The NPDS collects information from participating poison centers across the United States. HHS reviewed and analyzed the NPDS reports and found that annual number oftramadol exposures increased from 3,769 in 2004 to 9,623 in In 2008, intentional exposures to tramadol alone were 2,476. DEA further reviewed the recent NPDS data and found that the number oftramadol exposures continued to increase each year from 2009 through The numbers of human toxic exposures to tramadol were 10,255, 11,225 and 12,424 in 2009, 2010 and 2011, respectively. Of these totals, intentional exposures to tramadol alone were 2,677, 2,867 and 3,170 resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. The numbers ofexposures for tramadol during the years from 2009 to 2011 are less than the numbers ofexposures for hydrocodone (27, 753, 28,310 and 30,792, respectively) or oxycodone (18, 396, 19,363 and 19,424 respectively) products. b. There is a significant diversion oftramadolfrom legitimate drug channels. The National Forensic Laboratory Information System (NFLIS) is a DEA database that collects scientifically verified data on analyzed samples in state and local forensic laboratories. It also includes data from the System to Retrieve Information from Drug Evidence (STRIDE), which includes data on analyzed samples from DEA laboratories. The data show that for each ofthe years from 2000 through 2012, tramadol was present in drug exhibits seized in the course oflaw enforcement activity. Tramadol exhibits increased from a total of 82 in 2000 to 1,806 in The tramadol exhibits seized by law enforcement confirm the diversion oftramadol in the United States (U.S.). From 2008 to 2012, data from NFLIS and STRIDE show that the number oftramadol exhibits is greater than the pentazocine exhibits, but less than the corresponding numbers for hydrocodone, codeine, and buprenorphine. Data from both NFLIS and STRIDE also show that the annual number oftramadol exhibits during 2008 to 2010 is similar to that DEA/OD/ODE Page 4 of21 May 2013

5 of propoxyphene exhibits (Table 1). The number of propoxyphene exhibits(561) in 2011 is significantly less than that oftramadol exhibit (1.704) and this reduction is because in November 2010, FDA recommended that propoxyphene (Schedule IV or C-IV) be withdrawn from the U.S. market due to the risk ofcardiac toxicity. (Data queried as of March, 2013, from NFLIS and STRIDE database, Office of Diversion Control, DEA). Table 1. Data Sources: NFLIS (State and Local Laboratories) and STRIDE (DEA/Federal Laboratories), queried03/18/2013, by date ofsubmission, all drugs reported. Tramadol Exhibits NFLIS 1,148 1,255 1,450 1,632 1,754 STRIDE TOTAL 1,170 1,286 1,485 1,704 1,806 Buprenorphine Exhibits (Schedule III) NFLIS 4,702 7,355 10,033 10,285 9,588 STRIDE TOTAL 4,754 7,478 10,167 10,461 9,686 Codeine Exhibits (Schedule II, III,V) NFLIS 3,373 3,531 3,462 3,318 2,752 STRIDE TOTAL 3,545 3,678 3,679 3,452 2,867 Hydrocodone Exhibits (Schedule III) NFLIS 37,943 43,430 45,003 42,603 34,808 STRIDE TOTAL 38,424 44,081 45,627 43,292 35,258 Methadone Exhibits (Schedule II NFLIS 8,228 8,639 8,354 7,670 6,064 STRIDE TOTAL 8,406 8,785 8,483 7,785 6,144 Morphine Exhibits (Schedule II) NFLIS 5,496 6,919 7,151 7,675 7,612 STRIDE TOTAL 5,791 7,159 7,469 7,830 7,748 Oxycodone Exhibits (Schedule II) NFLIS 33,532 44,977 57,821 55,376 45,899 STRIDE 1,126 1,618 2,412 2,473 1,452 TOTAL 34,658 46,595 60,233 57,849 47,351 Pentazocine Exhibits (Schedule IV) DEA/OD/ODE Page 5 of21 May 2013

6 NFLIS STRIDE TOTAL Propoxyphene Exhibits (Schedule IV) NFLIS 1,331 1,426 1, STRIDE TOTAL 1,365 1,456 1, HHS review also suggests the possibility of diversion of tramadol by referencing updated information for the ULTRAM label that was approved on September 9, Under the heading of"physical Dependence and Abuse" is the following statement: Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug, are not limited to those patients with prior history ofopioid dependence. A post-marketing study published in 2002 cited by HHS review reported that among 140 health care professionals, who had at least one positive tramadol urine specimen, 87 cases were associated with illegal prescriptions for obtaining tramadol. According to another study cited by HHS review, diversion investigators from police agencies in all 50 states reported 42 cases oftramadol diversion in the first quarter and approximately 30 cases each in the remaining quarters during the period ofjanuary 2002 through March However, the number oftramadol diversion cases was less than the number of diversion cases associated with hydrocodone (C-III) and oxycodone (C-II) products. c. Individuals are taking tramadol on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs. HHS and DEA's evaluation found that current evidence indicates that individuals are taking tramadol on their own initiative without medical consultation. This evidence includes case reports ofabuse and dependence to tramadol in the medical literature as well as from epidemiological data (DAWN, NSDUH and AAPCC). HHS reviewed the DAWN data and found that over the period of2004 through 2008, the national annual estimates ofed visits related to nonmedical use oftramadol and its combinations increased from 4,849 to over 11,850. DEA further collected the DAWN data of2009 and 2010, and found that the national annual estimates ofed visits increased to 15,349 in 2009 and 16,251 in 2010, respectively. The National Survey on Drug Use and Health (NSDUH), operated by Substance Abuse and Mental Health Services Administration (SAMHSA), provides information on the nonmedical use ofdrugs in the United States population age 12 and older and its database provides annual estimates on the lifetime nonmedical use of opioids and pain relievers. HHS reviewed the NSDUH results and found that an estimated 1,559,000 DEA/OD/ODE Page 6 of21 May 2013

7 individuals had used tramadol nonmedically at least once in their lifetime in In addition, 57,000 individuals reporting initiation of any pain reliever use during the past year also had nonmedical use oftramadol. The 2007 result also revealed that both lifetime nonmedical use and nonmedical use over the past year among new initiates of pain reliever use, is lower for tramadol products when compared to oxycodone products (C-II), or to hydrocodone products (C-III). DEA further analyzed the updated NSDUH data and found that the estimated number of individuals who have used tramadol products non-medically at least once in their lifetime are 1,990,000; 2,181,000; 2,282,000 and 2,614,000 in 2008, 2009, 2010 and 2011, respectively. Furthermore, these numbers are lower than that of oxycodone (C-II) and hydrocodone products (C-III). AAPCC manages the National Poison Data System (NPDS), which is the only near real-time comprehensive poisoning surveillance database in the U.S. HHS reviewed the NPDS reports and found that for 2006, 2007, and 2008, there were 1,482, 1,847, and 2,476, respectively, case mentions involving intentional exposure to tramadol alone. DEA further evaluated the NPDS data and found that in 2009, 2010 and 2011, the number of reported tramadol poison exposures totaled 10,255, 11,225 and 12,424, respectively. Of these totals, intentional exposures to tramadol alone were 2,677, 2,867 and 3,170 resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. The number of exposures for tramadol in 2011 was less than the number of exposures for hydrocodone (C-III) or oxycodone (C-II). These findings indicate that tramadol poses a significant threat to the public health. d. Tramadol is so related in its action to a drug or other substance already listed as having apotentialfor abuse to make it likely that it will have the same potentialfor abuse as such substance, thus making it reasonable to assume that there may be significant diversionsfrom legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety ofthe community. According to HHS review, tramadol shares many similar pharmacological activities with some opioids that were scheduled under the CSA. As such, the abuse potential of tramadol would be expected to be related to its opioid properties. Therefore, tramadol would be expected to be diverted from legitimate sources and be used without medical supervision, and would subsequently represent a safety concern to individuals and the community. According to HHS review, the opioid activity of tramadol is primarily due to its metabolite, O-desmethyltramadol or "Ml." Compared to other opioids, tramadol showed a longer onset ofaction due to accumulation ofthe active metabolite and its effects include analgesia, respiratory depression, miosis, cough suppression, and inhibition of bowel motility. Preclinical studies demonstrate that tramadol, as other opioids in schedules I through IV, exhibits complete generalization to morphine (C-II) and be able to produce some reinforcing effects. Repeated administration of tramadol in animals caused dependence development, evidenced by a withdrawal syndrome similar in intensity to pentazocine (C-IV) or propoxyphene (C-IV). Human studies reveal that tramadol produces some reinforcing subjective effects at high doses. A similar dose DEA/OD/ODE Page 7 of 21 May 2013

8 response pattern at high doses with propoxyphene (C-IV) to produce reinforcing subjective effects was also observed. Thereby, propoxyphene may serve as an appropriate comparator drug for tramadol with respect to generating reinforcing effects. According to HHS review, several studies examining abuse potential suggest that the subjective reinforcing effect oftramadol is less than that of schedule II opioids and more comparable to that ofpropoxyphene (C-IV). In summary, the abuse potential oftramadol is similar to that of substances in schedule IV (such as propoxyphene) ofthe CSA. The accumulated information demonstrates that individuals are taking tramadol nonmedically and in amounts sufficient to create a hazard to their health. Tramadol is diverted from legitimate sources and produces effects similar to other CSA-controlled opioids known to have an abuse potential. Furthermore, the available information regarding reinforcing effects and drug dependence shows that the abuse potential oftramadol is less than that ofmorphine (C-II), oxycodone (C-II) or buprenorphine (C-III), but similar to that ofpropoxyphene (C-IV). Additionally, epidemiological data also support an abuse potential for tramadol that is similar with substances in schedule IV ofthe CSA. Factor 2: Scientific Evidence oftramadol's Pharmacological Effects According to HHS review, tramadol is an opioid analgesic and produces opioid-like effects primarily due to its metabolite, O-desmethyltramadol or "Ml" (not scheduled). HHS found that tramadol, similar to some CSA-controlled opioids, produces many pharmacological effects which are listed below: Receptor Binding: The primary receptor binding site oftramadol and O- desmethyltramadol (Ml) is the tr-opioid receptor. The affinity ofmorphine (C-II) is approximately times greater than Ml and 300 times greater than tramadol. Tramadol was approximately 10-fold less potent than codeine (C-II), 1000-fold weaker than methadone (C-II), and 6000-fold weaker than morphine (C-II). The Ml metabolite had a high intrinsic efficacy at the human opioid receptors and it was between the relative intrinsic efficacies ofmorphine (C-II) and fentanyl (C-II). HHS concluded that Ml metabolite primarily accounts for the u-opioid component ofthe analgesic effects of tramadol. Inhibition of Serotonin and Norepinephrine Reuptake: Studies have shown that tramadol inhibits in vitro neuronal reuptake of norepinephrine and serotonin. O-desmethyltramadol (Ml) is effective in both blocking reuptake and blocking release of norepinephrine and serotonin. Tramadol, with the concomitant use of serotonergic drugs such as serotonin re-uptake inhibitors and monoamine oxidase inhibitor (MAO) inhibitors may enhance the risk ofadverse events, including seizure and serotonin syndrome. Similar to tramadol, other opioids such as methadone (C-II), meperidine (C-II), and levorphanol (C-II) inhibit serotonin and norepinephrine reuptake (HHS review, 2010). Analgesia: Preclinical studies found that in animals with painful stimulation, tramadol demonstrated a dose-related anti-nociceptive effect. The animal models DEA/OD/ODE Page 8 of21 May 2013

9 included tail-pressure, paw-pressure, and electrically induced vocalization tests in rats; tail-flick, hot-plate, and abdominal constriction tests in mice and rats; and the electrical tooth-pulp stimulation test in rabbits. In a HHS cited study, the intravenous administration ofeither tramadol or Ml produced dose-dependent analgesia and the following descending order ofanalgesic activity was found: hydromorphone (C-II) > hydrocodone (C-II) > morphine (C-II) > Ml > codeine (C-II) = tramadol. According to the HHS review, many clinical studies demonstrate the analgesic effects oftramadol when treating various pain states in humans. The analgesic effect of tramadol involves both opioid mechanisms, via the Ml metabolite, and the mechanism ofnorepinephrine and serotonin reuptake blockade. The production ofanalgesia is consistent with Ml formation, which commences within one hour of post-administration and peaks at 2 to 3 hours later. The analgesic effects of tramadol were compared to opioid analgesics in schedules III and IV. In several large clinical trials for treatment ofacute pain, tramadol was significantly less effective than that of hydrocodone/acetaminophen (C-III), but displayed an analgesic effect similar to that ofpentazocine (C-IV) or, superior or similar to proproxyphene/acetaminophen combination (C-IV) in relieving postoperative pain. Miotic Effect: As stated in the HHS review, like morphine and most p-opioid agonists, tramadol was also shown to cause pupillary restriction, but the onset ofwhich is delayed several hours following tramadol administration. Urinary Effect: Tramadol and morphine (C-II) caused urinary retention in rats via a similar mechanism ofactivating p-opioid receptors since a pretreatment with naloxone blocked this effect. Human urinary retention induced by tramadol was also reported in the medical literature (HHS review, 2010). Respiratory Effect: Similar to other opioids that depress respiration, tramadol causes a dose-response respiratory depression both in laboratory animals and patients. Considering that naloxone partially blocks the respiratory depression caused by tramadol, it was suggested that both monoaminergic and opioid mechanisms contributed to the respiratory effects oftramadol (HHS review, 2010). Other Effects: Other effects oftramadol including anti-tussive effect, nauseant and emetic effects and intestinal effects were also reported extensively in medical literature referenced by HHS review. Several pre-clinical and clinical studies evaluating tramadol's abuse liability in laboratory animals and human were documented in the HHS review and summarized below: Drug Discrimination Studies: Several drug discrimination studies using rats indicate that tramadol displays symmetrical generalization to morphine (C-II). A study using rats reported that a full generalization was achieved with morphine at doses of 2.37 mg/kg or higher and with tramadol at doses of 32 mg/kg or higher. The generalizations by morphine and tramadol were blocked by the concomitant administration of naltrexone ( mg/kg). Another study cited by HHS confirmed that tramadol generalized to DEA/OD/ODE Page 9 of21 May 2013

10 morphine (C-II) through a p-opioid receptor mechanism. These studies indicate that the discriminative stimulus cues of tramadol are typical of classical opioids like morphine. Drug Self-Administration Studies: According to HHS review, there are published reports documenting the intravenous self-administration of tramadol in Rhesus monkeys. Based on review of these studies, HHS stated that tramadol produces limited reinforcing effects as compared to schedule II and III opioids, thereby supporting placement of tramadol in a lower schedule level. Human Abuse Potential Studies - Subjective Reinforcing Effects oftramadol In post-approval studies ofa tramadol containing product, the abuse potential of intravenous tramadol was compared to that of intravenous morphine. One single-blind study showed that at the higher intravenous dose of 400 mg, tramadol produced opiate like effects, including "liking" and a euphoric "high", that transiently surpassed that produced by 20 mg morphine. Lower doses oftramadol were less effective in producing these effects. According to HHS review, in light of the high doses of tramadol relative to morphine required to produce reinforcing effects, tramadol has an abuse potential but it is less than that of morphine (C-II). Another double-blind, single-dosed study found that tramadol at intravenous doses of 100 mg and 200 mg has a lower abuse potential, than that ofintravenous morphine (C-II) at doses of 10 mg and 20 mg in non-dependent, opioid experienced subjects. When comparing the abuse potential of oral tramadol to that of oral oxycodone (C-II) in non-dependent, opioid experienced volunteers, the results indicated that the effect of tramadol was slower in onset and longer in duration. Tramadol (750 mg) also produced "liking" which was slower in onset and of longer duration than that produced by oxycodone (C-II). Both studies provided support that tramadol, particularly at the higher doses, produces subjective reinforcing effects, thereby indicating an abuse potential for tramadol. According to HHS review, tramadol at high doses produces subjective reinforcing effects similar to or approaching those of morphine (C-II) and oxycodone (C-II). In summary, pharmacological and efficacy studies indicate that tramadol primarily acts via its Ml metabolite to interact with the p-opioid receptor to produce a variety of pharmacological effects commonly produced by CSA-controlled opioids listed in schedules II-IV. There tends to be a time delay in the appearance ofthese effects, indicating the importance ofthe Ml metabolite in evoking the effects. Generalization to the morphine stimulus cue provides additional support indicating that tramadol produces effects similar to opioids (C-II, -III, and -IV). Additionally, tramadol can block the reuptake ofnorepinephrine and serotonin and similar effects are also produced by such opioids as meperidine (C-II), methadone (C-II) and levorphanol (C-II). The reinforcing effect oftramadol was limited. No animal self-administration studies utilizing an opioid positive control in schedules II, III, IV or V have evaluated the reinforcing effects of tramadol. The limited reinforcing effects oftramadol observed in the self-administration studies suggest placement oftramadol in a schedule less restrictive than morphine(c-ii). Clinical studies also show that tramadol, at single high doses, produces subjective reinforcing effects that are significantly greater than those ofplacebo and are similar to or DEA/OD/ODE Page 10 of21 May 2013

11 approach those produced by morphine (C-II) and oxycodone (C-II), respectively. A similar dose response in producing subjective reinforcing effects occurs with propoxyphene (C-IV) at elevated doses and this fact provides support for a similar abuse potential and placement oftramadol into schedule IV ofcsa. Factor 3: The State of Current Scientific Knowledge Regarding Tramadol The chemical name of tramadol hydrochloride is (±) c/s-2-((dimethylamino) methyl)- l-(3-methoxyphenyl)-cyclohexanol hydrochloride. Tramadol hydrochloride has a molecular formula of C16H25NO2 HC1 with a molecular weight of Because of its chemical structure, it can exist as different isomeric forms. Thus, various prefixes can be associated with the name. Some example ofthese prefixes include dextro, levo, d, 1, R, S, cis, trans, erythro, threo, (+), (-), Racemic, and may include combinations ofthese prefixes sometimes with numerical designations. Using a prefix that identifies an isomeric form in the name does not change the fact that it is 2-((dimethylamine)-mefhyl)- l-(3-methoxyphenyl)-cyclohexano. Tramadol is typically identified as (±) cis-2- ((dimefhylamino) methyl)-l-(3-methoxyphenyl)-cyclohexanol hydrochloride. Registry numbers for tramadol are CAS (hydrochloride salt) and CAS (base). Tramadol hydrochloride is a white, bitter, crystalline and odorless powder soluble in water and ethanol. According to HHS review, a linear pharmacokinetic pattern oftramadol has been observed following multiple doses of 50 mg and 100 mg to a steady-state. Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability ofa 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and Ml occurs at two and three hours, respectively, after administration in healthy adults. The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding oftramadol to human plasma proteins is approximately 20% and the binding capability also appears to be independent of concentration up to 10 pg/ml. Tramadol is extensively metabolized after oral administration. Approximately 30% ofthe dose is excreted in the urine as unchanged drug, whereas 60% ofthe dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, or denoted Ml) is pharmacologically active in animal models. Formation ofml is dependent on cytochrome P450 2D6 (CYP2D6) and as such is subject to inhibition, which may affect the therapeutic response. Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic Ml are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. Tramadol is rapidly absorbed with a high bioavailability following rectal administration and intramuscular injection. In summary, tramadol hydrochloride is readily absorbed from the gastrointestinal tract, or via subcutaneous, intramuscular and rectal routes. As the primary metabolite of tramadol, Ml is primarily responsible for the opioid activity oftramadol. The DEA/OD/ODE Page 11 of 21 May 2013

12 metabolism oftramadol, in part, may interact with other drugs that undergo metabolism by the CYP2D6 enzyme. Factor 4: Tramadol's History and Current Pattern of Abuse FDA approved ULTRAM (immediate-release oral tablets oftramadol) in 1995 for the treatment of moderate to moderately severe pain. Since that time, a variety of other tramadol products including immediate release forms, combination products and extended release products have been approved for marketing in the U.S. HHS collected and analyzed the data regarding tramadol prescriptions in the United States and it included tramadol as an active ingredient in both immediate-release and extended-release pharmaceutical products. HHS performed a comparison between tramadol and other analgesics in terms ofannual prescriptions dispensed over the period of2003 to 2008 from SDI prescription database. It was found that in 2007 and 2008, more prescriptions were written for tramadol than for any other opioid other than hydrocodone (C-III) and oxycodone (C-II). The annual number ofprescriptions for tramadol surpassed the annual number ofprescriptions ofproproxyphene (C-IV) and codeine products (C-II, -III, and -V) in 2007 and In contrast to the consistent incremental rise in annual prescriptions seen for tramadol over the period of 2003 to 2008, there was a consistent reduction in annual prescriptions for proproxyphene, butorphanol (C-IV) and pentazocine (C-IV) over the same period. Whereas there was a slight rise in the number of prescriptions in 2008, there has been a consistent reduction in annual prescriptions for codeine products (C-II, -III, and -V) over the period from 2003 to Over each ofthe five years, there has been a consistent multi-fold greater number ofprescriptions written for tramadol compared to such analgesics as morphine (C-II), fentanyl (C-II), methadone (C-II), hydromorphone (C-II), buprenorphine (C-III), meperidine (C-II), butorphanol (C-IV), pentazocine (C-IV), and oxymorphone (C-II). DEA further collected and analyzed updated data from IMS Health's National Prescription Audit Plus, another major national prescription database and found a similar trend from 2009 to 2011, as revealed by HHS's document, that more prescriptions were dispensed for tramadol than for any other opioid other than hydrocodone (C-III) and oxycodone (C-II). DAWN managed by SAMHSA is a public health surveillance system that monitors drug-related visits to hospital emergency departments (ED). HHS reviewed DAWN data and found that abuse-related ED visits involving tramadol increased from 1995 (645 cases) to 2002 (1714 cases) peaking in 2001 (2329 cases). Tramadol abuse-related deaths increased from 45 cases (1997) to 88 cases (2002). Over the period of2004 through 2008, the number ofestimated ED visits from nonmedical use oftramadol/combinations showed a continuous increase from 4,849 ED visits to 11,850 ED visits. For each ofthe years from 2004 through 2008, the annual nonmedical ED visits for tramadol/combinations were well below that for fentanyl/combinations (C-II), hydrocodone/combinations (C-III), morphine/combinations (C-II), and oxycodone/combinations (C-II). DEA further collected the DAWN data of2009 and 2010, and found that the national annual ED visits increased to 15,349 in 2009 and 16,251 in 2010, respectively. DEA/OD/ODE Page 12 of21 May 2013

13 HHS reviewed DAWN data and calculated the rates of estimated nonmedical ED visits per 100,000 prescriptions dispensed for tramadol/combinations as well as other selected opioids. HHS found that over the period of 2004 through 2007, the annual rates oftramadol/combination ED visits ranged between 28.4 and 33.9 per 100,000 prescriptions. In 2008, there was a substantial increase in rate ofed visits of tramadol/combinations to 45.8 ED visits per 100,000 prescriptions. Over the five year period ( ), annual rates of tramadol ED visits were substantially below that of rates for oxycodone/combinations (C-II), methadone (C-II), hydromorphone (C-II), morphine (C-II), fentanyl/combinations (C-II), meperidine/combinations (C-II), hydrocodone combinations (C-III) and buprenorphine/combinations (C-III) ( only). Over the period of 2004 through 2008, the rates of estimated nonmedical ED visits for tramadol/combinations were more closely in the range for the rates of codeine/combinations (C-II, -III, and -V) and proproxyphene/combinations (C-IV) compared to the other opioids for which data was provided and showed substantially higher rates. For all three drugs, there was an increase in rates of ED visits in 2008 compared to In 2008, the rate of nonmedical ED visits per 100,000 prescriptions of tramadol/combinations was 45.8 which was between that for proproxyphene/combinations (62.7 ED visits per 100,000 prescriptions) and that for codeine/combinations (40.2 ED visits per 100,000 prescriptions). HHS reviewed the annual NSDUH report and found that the number of individuals who used tramadol nonmedically at least once in their lifetime increased from approximately 994,000 in 2002 to 1,559,000 in For each year surveyed, the absolute number regarding tramadol was lower than that ofhydrocodone or oxycodone. Additionally, for each ofthe years over the period of2002 to 2007, the estimated number of individuals who initiated use and reported nonmedical use oftramadol was less than 100,000 (with the highest at 95,000 in 2003 and the lowest at 22,000 in 2006). By contrast, for each ofthe years from 2002 to 2007, the number ofpast year initiates for use ofany pain reliever who also used hydrocodone (> 1,200,000) and oxycodone (> 450,000) nonmedically was greater than that oftramadol. In summary, the information from the NSDUH shows that tramadol is used nonmedically. The lifetime nonmedical use and past year nonmedical use oftramadol among new initiates ofpain reliever use is lower than that for oxycodone products (C-II) and hydrocodone products (C-III) and supports placement oftramadol in a schedule less restrictive than schedule III. As stated in Factor 1, the DEA-managed NFLIS and STRIDE databases provide evidence that tramadol has been diverted and encountered by law enforcement personnel. Such as in 2010, forensic laboratories analyzed 1,485 such exhibits and the tramadolcontaining exhibits were approximately similar in number to that of propoxyphene (Table 1). For each year, the number of tramadol exhibits was less than that of the schedule II substances, oxycodone, methadone, morphine, hydromorphone, hydrocodone, and codeine (C-II, -III, and -V). The relatively lower numbers of propoxyphene exhibits in 2011 and 2012 is because in November 2010, FDA recommended that propoxyphene (C- IV) be withdrawn from the United States market due to the risk of cardiac toxicity. DEA/OD/ODE Page 13 of21 May 2013

14 These exhibits from criminal investigations involving tramadol provide evidence ofthe significant diversion and nonmedical use oftramadol in the U.S. HHS reviewed toxic exposure calls data from the National Poison Data System (NPDS), a database ofthe American Association of Poison Control Centers (AAPCC), and found that the number ofcase mentions ofhuman toxic exposures to tramadol during 2004 through 2008 increased annually from 3,769 to 9,623. These are less than the case mentions oftoxic exposures to hydrocodone (C-III) or oxycodone (C-II). Of 5,965, 7,500 and 9,623 total case mentions for tramadol in 2006, 2007, and 2008, respectively, 1,482, 1,847, 2,476 involved "intentional" exposure to tramadol alone. DEA further reviewed the recent NPDS data and found that in 2009, 2010 and 2011, the number of reported tramadol poison exposures totaled 10,255, 11,225 and 12,424, respectively. Of these totals, intentional exposures to tramadol alone were 2,677, 2,867 and 3,170 resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. Furthermore, the numbers oftoxic exposures for tramadol in 2009, 2010 and 2011 are also less than the corresponding numbers for hydrocodone or oxycodone. HHS further found that the rates oftoxic exposures calculated as number ofcase mentions per 100,000 prescriptions for tramadol increased from 22 in 2004 to 37 in These rates oftoxic exposures for tramadol during the period of 2004 through 2007 were lower than the corresponding rates for oxycodone (C-II), morphine (C-II) and methadone (C-II). For the years 2004, 2005, and 2006, the rates oftoxic exposures to tramadol were similar to that ofpropoxyphene (C-IV). In 2007 and 2008, tramadol surpassed codeine (C-II, -III, and -V) and propoxyphene (C-IV) in the number and rate oftoxic exposures. These data indicate that tramadol represents a significantly growing risk to the public health. Overall, data from DAWN, NSDUH, NFLIS, STRIDE and AAPCC-NPDS databases collectively demonstrate the abuse, and diversion oftramadol in the U.S. With respect to both the rates ofnonmedical ED visits as reported in DAWN and the number of forensic drug exhibits, and the rates oftoxic exposures, tramadol data most closely resembles that ofpropoxyphene (C-IV). Data from the NSDUH also supports a schedule less restrictive than that of schedule II or III. Factor 5: The Scope, Duration, and Significance of Abuse oftramadol An assessment of the scope, duration, and significance oftramadol abuse is made by examination ofdatabases that document abuse, review of studies of abuse potential, and consideration ofthe case reports described in HHS review document. HHS stated that there is almost 15 years ofpost-marketing epidemiologic abuserelated data in the scientific literature and from the adverse events reporting system (AERS) since tramadol's commercial availability in the U.S. The case reports describe abnormal behavior that demonstrates an addiction liability oftramadol: drug craving, increasing the tramadol dose, performing self-injury in order to be prescribed more tramadol, taking high doses despite adverse effects that result, and visiting multiple physicians in order to obtain more prescriptions for tramadol. Approximately 15 years of post-marketing history now show that tramadol can and is being abused both in the DEA/OD/ODE Page 14 of21 May 2013

15 United States and other countries. The increasing evidence includes epidemiologic abuse-related data in the published scientific literature, as well as data from national and state data systems that track drug abuse. Case reports in the medical literature provide information on patterns oftramadol abuse when prescribed for clinical pain management. The case reports listed by HHS review describe abuse of tramadol for its euphorigenic and sedating effects. The depicted behavior illustrates an addiction to tramadol: drug craving, increasing the tramadol dose, inflicting self-injury in order to be prescribed more tramadol, taking high doses despite adverse effects that result, and visiting multiple doctors in order to obtain more prescriptions for tramadol. These reports provide information on characteristics and patterns of actual tramadol abuse with the development of dependence. Development of iatrogenic addiction to tramadol due to medical treatments is also described in HHS review. The NSDUH data, discussed in detail in Factor 4, also provides evidence of the nonmedical use oftramadol. According to the updated NSDUH data analyzed by DEA, the estimated number of individuals who have used tramadol products non-medically at least once in their lifetime increased from 1,990,000 in 2008 to 2,614,000 in For each year from 2002 to 2011, the number of individuals reporting lifetime nonmedical use oftramadol resulting from the NSDUH survey was lower than the corresponding numbers for hydrocodone or oxycodone. According to DAWN data, in 2008, an estimated 11,850 ED visits nationally were for nonmedical use of tramadol. There is an increasing trend ofannual nonmedical ED visits from 2004 through With regard to the national estimates ofed visits of nonmedical use and the rates ofthese visits per 100,000 prescriptions, the rate for tramadol is similar to propoxyphene/combination and codeine/combination. DEA further found that the national annual estimates ofed visits involving tramadol in 2009 and 2010 increased to 15,349 and 16,251 respectively. These data from several databases collectively suggest that tramadol has abuse potential and it adversely affects the public health. These data further support the scheduling oftramadol with a schedule IV control of CSA. Factor 6: What, If Any, Risk to the Public Health According to HHS review, information from a variety of sources and medical literature shows that there is a risk to public health associated with the abuse oftramadol due to its adverse effects similar to other opioids. As stated in the HHS review, adverse effects associated with the use of tramadol are documented in the label ofa tramadol containing product approved by FDA in September 9, Adverse effects occurring with tramadol are consistent with adverse effects associated with other opioids. The incidence of reported adverse effects increased as the time oftramadol therapy increased. The overall incidence rates of adverse effects DEA/OD/ODE Page 15 of21 May 2013

16 of tramadol were similar with codeine containing drugs such as codeine phosphate 30 mg with acetaminophen 300 mg (C-III). and codeine phosphate 30 mg with aspirin 325 mg (C-III). Other adverse effects associated with tramadol included seizures, serotonin syndrome, and respiratory depression. In a study oftramadol overdose from seven U.S. poison centers over the period from October 1995 through August 1996, 126 cases of overdosed tramadol presented multiple systematic symptoms ranging from cardiovascular toxicity to significant neurologic toxicity including lethargy, nausea, tachycardia, agitation, seizures, coma, hypertension and respiratory depression. The mechanism underlying tramadol overdose toxicity is closely related to its p-opioid receptor activity and its monoamine oxidase inhibitor (MAOI) activity. Information from DAWN database shows that the rates ofed visits due to nonmedical use oftramadol have been similar to that of propoxyphene (C-IV) but lower than that of schedule II and III opioids during the period of HHS reviewed the number ofdrug abuse deaths from DAWN database reported by the participating medical examiners and coroners in selected areas and found a total of 395 tramadol abuse-related deaths were reported to DAWN from 1997 to The DAWN data demonstrates a risk to the public health associated with the nonmedical use oftramadol that is similar to that of propoxyphene (C-IV). The HHS reviewed the AAPCC's NPDS data and found that there was an increasing public health risk associated with tramadol. Annual tramadol exposures increased from 3,769 in 2004 to 9,623 in DEA further reviewed the recent NPDS data and found that the number oftramadol exposures continued to increase each year from 2009 through The numbers of human toxic exposures to tramadol were 10,255, 11,225 and 12,424 in 2009, 2010 and 2011, respectively. Ofthese totals, intentional exposures to tramadol alone were 2,677, 2,867 and 3,170 resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. The HHS found that tramadol ranked third behind hydrocodone (C-III) and oxycodone (C-II) in terms ofthe number ofpoison case mentions ofopioids in 2007 and Over this period, the rates ofcase mentions per 100,000 prescriptions for tramadol increased from 22 to 37. In addition, the rate of tramadol case mentions was lower than that for oxycodone (C-II), morphine (C-II) and methadone (C-II). In 2008, the rate oftramadol case mentions was less than that of methadone (C-II) and morphine (C-II). For the years 2004, 2005, and 2006, the rates of tramadol case mentions were similar to that of propoxyphene (C-IV). The labeling information approved by FDA states that tramadol in excessive doses either alone or in combination with other central nervous system depressants, including alcohol, are a cause ofdrug-related deaths. Furthermore, a number ofreports in the medical literature have documented deaths associated with tramadol. Other reports document tramadol as a contributing factor to deaths in combination with other drugs such as, but not limited to, benzodiazepines, serotonergic drugs and other antidepressants. The annual number of tramadol-related deaths reported by medical examiners in the DAWN database gradually increased from 1997 to DEA/OD/ODE Page 16 of21 May 2013

17 The HHS also reviewed tramadol associated mortality from the Florida Department of Law Enforcement (FDLE). FDLE collects information on drug-related deaths as reported by medical examiner offices across the state of Florida. The number ofdeaths involving tramadol increased from 106 in 2003 to 235 in According to FDLE's data, tramadol-related deaths were higher than heroin (C-I) related deaths in years from 2005 to For each ofthe years, the number of deaths involving tramadol was less than the number of deaths involving hydrocodone (C-III), fentanyl (C-II), morphine (C- II), oxycodone (C-II), methadone (C-II), and propoxyphene (C-IV), but higher than the number ofdeaths involving meperidine (C-II) and hydromorphone (C-II) (except for 2007). DEA further reviewed the data for the recent years 2009, 2010 and 2011 and found that tramadol-related deaths continued to increase. There were 268, 275, 379 tramadol-related deaths in 2009, 2010 and 2011, respectively. In summary, the above mentioned data from a number ofsources indicate that tramadol presents risks to the public health and, as such, supports the scheduling of tramadol as a schedule IV substance under the CSA. Factor 7: Tramadol's Psychic or Physiological Dependence Liability According to HHS review, current information from pre-clinical and clinical studies demonstrates that the repeated dosing with tramadol resulted in dependence development as well as withdrawal syndrome following either abrupt termination oftramadol treatment or administration of opioid antagonist. Furthermore, medical literature also documents numerous case reports of physiological and physical dependence to tramadol. As stated in HHS review document, a preclinical study of spontaneous withdrawal of tramadol in Rhesus monkeys found that the tested animals displayed "mild" or "intermediate" withdrawal signs after the termination oftramadol administration for 8 weeks. This study demonstrated that tramadol has the potential to produce some physical dependence as evidenced by naloxone precipitated withdrawal. Another finding in rats cited by the HHS review indicating milder withdrawal signs with termination oftramadol also confirmed that a physical dependence could be developed following repeated oral administration oftramadol. In a withdrawal jumping test with mice, the results showed that the number ofjumps in tramadol-treated animals was comparable with that of propoxyphene (C-IV) and lower than that ofcodeine (C-II), methadone (C-II), and morphine (C-II). Another naloxone precipitated jumping assay indicated that tramadol produced a degree ofphysical dependence similar to that ofpropoxyphene (C-IV). Furthermore, a short-term frequent intravenous infusion of tramadol in rats found that the total withdrawal scores oftramadol were lower than that ofmorphine (C-II) following naloxone administration. By comparing physical dependence development resulting from repeated subcutaneous administration of either morphine (C-II) (100 and 1.05 mg/kg) or tramadol (100 or 39.1 mg/kg) to mice, another study concluded that tramadol produced a lesser degree of physical dependence than morphine. These HHS-referenced preclinical studies show that repeated exposure to tramadol results in mild to moderate levels of physical dependence as evidenced by spontaneous or precipitated withdrawal. These data also suggest that the degree ofdependence development oftramadol is less DEA/OD/ODE Page 17 of21 May 2013

18 than that of schedule II and schedule III, but similar to that of schedule IV drugs such as pentazocine (C-IV) and propoxyphene (C-IV). According to HHS review, a number ofclinical studies examined the ability of tramadol to substitute for other opioids in individuals who are opioid dependent. A study compared the effectiveness oftramadol versus buprenorphine in the treatment ofopiate withdrawal and reported that tramadol and buprenorphine (C-III) effectively managed acute opioid withdrawal displayed by patients with mild to moderate addiction to heroin (C-I). Another study compared the use oftramadol to that ofclonidine for management ofacute heroin (C-I) withdrawal and found that tramadol was more effective in managing withdrawal than clonidine (not scheduled), and may be useful in outpatient detoxification. In examining tramadol for opioid withdrawal suppression in opioiddependent adults, one study revealed a cross dependence development between tramadol and other opioids, such as morphine. A modest suppression ofopioid withdrawal produced by tramadol was also reported in subjects with a mild to moderate degree of opioid physical dependence. The HHS review cites several published case reports that provide evidence ofcross dependence development between tramadol and opioids, as seen by suppression of withdrawal symptoms upon termination ofextended tramadol treatment. Such as, one case report indicated a cross-dependence development oftramadol to methadone (C-II) and another study documented that the use of buprenorphine/naloxone (C-III) to alleviate withdrawal symptoms caused by prolonged use of high doses oftramadol. According to HHS review, as of September 9, 2009, 'Withdrawal symptoms may occur" was documented in the "Warning" section ofthe label for a tramadol containing product. Combining studies ofcross dependence, tramadol produces a modest suppression ofwithdrawal in subjects dependent on other opioids. This suppression appears less than that produced by morphine (C-II) or buprenorphine (C-III). The available studies indicate that tramadol shows some cross dependence to heroin, methadone, morphine and buprenorphine. Collectively, all ofthe preclinical and clinical data show that tramadol produces a modest level of physical dependence. These studies also suggest a degree ofphysical dependence development less than that of schedule II and III opioids and similar to that of schedule IV opioids. Factor 8: Whether Tramadol Is an Immediate Precursor of a Substance Already Controlled Tramadol is not an immediate precursor ofa substance already controlled. III. Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b) DEA/OD/ODE Page 18 of21 May 2013

19 21 U.S.C. 812(b) requires the evaluation ofa substance's abuse potential, accepted medical use, and safety for use under medical supervision for placement in the CSA as a controlled substance. After consideration ofthe above eight factors determinative of control ofa substance (21 U.S.C. 811(c)), and a review ofthe scientific and medical evaluation and scheduling recommendation provided by the HHS, DEA finds that tramadol meets the following criteria for placement in schedule IV ofthe CSA, under 21 U.S.C. 812 (b)(4). 1) Tramadol has a potential for abuse less than the drugs or other substances in Schedule III. The collected information suggests that tramadol meets the criteria and indicators set forth in the legislative history ofthe CSA for having an abuse potential. Individuals take tramadol without medical supervision and in amounts sufficient to create a hazard to their health as evidenced from various study reported in the medical literature, nonmedical use in databases from DAWN, NSDUH and AAPCC. Tramadol has been diverted from legitimate sources as evidenced by numerous reports in the medical literature as well as in epidemiology and legal databases including NFLIS, STRIDE, DAWN, NSDUH and AAPCC. Both pre-clinical and clinical studies show that tramadol, via its Ml metabolite, produces a variety of pharmacological and toxicological effects similar to that of CSAcontrolled opioids known to have an abuse potential. Collectively, the available information regarding tramadol supports an abuse potential that is less than that of schedule III and similar to that for schedule IV. Preclinical selfadministration studies show that tramadol produces limited reinforcing effects, consistent with a lower schedule. Tramadol can produce subjective reinforcing effects similar to that of morphine (C-II) and approaching that ofoxycodone (C-II) at supra-therapeutic doses. A similar dose dependency occurs with propoxyphene (C-IV), in which high doses but not therapeutic doses produce subjective reinforcing effects. For both tramadol and propoxyphene, the doses required to produce significant subjective reinforcing effects are in a range causing sufficient adverse effects. These observations indicate that the subjective reinforcing effects, a reflection of abuse potential, of tramadol is less than that of morphine or oxycodone, but similar to that of propoxyphene. Dependence is one of the driving forces leading to the tramadol abuse and scientific information related to tramadol dependence provides evidence for tramadol's potential of abuse. Several case reports describe physical and psychological dependence to tramadol resulting from human abuse of high doses of tramadol. Opioid withdrawal suppression caused by tramadol was indicated in several clinical investigations and the degree was less than that produced by morphine or buprenorphine (C-III). The current clinical studies on tramadol dependence suggest its abuse potential lower than that of schedule III drugs, but similar to that of schedule IV. Scientific evidence for indicating an abuse potential for tramadol at a level of schedule IV is also supported by collected data from several epidemiological databases. The NSDUH data indicates that the number ofindividuals reporting lifetime misuse of DEA/OD/ODE Page 19 of 21 May 2013

20 tramadol was below that ofthe number ofeither oxycodone or hydrocodone. The NSDUH result supports a scheduled level for tramadol less restrictive than schedule III. The DAWN data also shows that the rate of ED visits related to tramadol is lower than that ofopioids in schedules II and III, but similar to that ofpropoxyphene. The 2008 NFLIS data demonstrate that the number of seized tramadol by law enforcement agencies was close to that of propoxyphene, thereby supporting a schedule IV control for tramadol. 2) 2) Tramadol has a currently accepted medical use in treatment in the United States. The FDA approved tramadol for marketing for the management ofmoderate to moderately severe pain in Since then, FDA has approved a number ofadditional products containing tramadol. As such, tramadol has a currently accepted medical use in treatment in the United States. 3) Abuse of tramadol may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III. Tramadol may lead to development ofphysical and psychological dependence as documented in current product labels. In addition, several clinical case reports indicate the development of physical and psychological dependence to tramadol. Both animal and clinical studies also provide support that tramadol induces an opioid-like dependence. The available information regarding reinforcing effects and drug dependence suggests that the degree ofphysical dependence produced by tramadol is low, supporting placement oftramadol in schedule IV. DEA/OD/ODE Page 20 of21 May 2013

21 References j. Department of Health and Human Services, FDA Review (2010): Basis for the Recommendation to Schedule Tramadol In Schedule IV of the Controlled Substances Act. Data queried for tramadol (March, 2013), The National Forensic Laboratory Information System (NFLIS), Office of Diversion Control, Drug Enforcement Administration. Data queried for tramadol (March, 2013), The System to Retrieve Information from Drug Evidence (STRIDE), Office of Diversion Control, Drug Enforcement Administration. DEA/OD/ODE Page 21 of 21 May 2013