Tramadol in New Zealand 2007 Strategic Assessment
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NEW ZEALAND
NATIONAL DRUG INTELLIGENCE BUREAU
JOINT OPERATION OF POLICE, CUSTOMS & HEALTH DEPARTMENTS
Police National Headquarters, 180 Molesworth Street, Wellington, New Zealand
PO Box 3017, Phone: 64 4 462 0131, Fax: 64 4 498 7409
Tramadol in New Zealand
2007 Strategic Assessment
Martin Woodbridge
Drug Intelligence Analyst
December 2007
Released by: Coordinator, NDIB
Page 1 of 22CONTENTS
GLOSSARY .................................................................................................................... 3
1.0 INTRODUCTION ....................................................................................................... 4
2.0 SUBSTANCE IDENTIFICATION ............................................................................... 5
2.1 The Chemical Name/Trade Names for Tramadol................................................... 5
2.2 The Origin and History of Tramadol ....................................................................... 5
2.3 The Chemical Makeup of the Active Components: Tramadol................................. 6
2.4 Tramadol’s Similarity to Other Known Substances ................................................ 6
2.5 Consumption and Administration of Tramadol (Licit and Illicit Use)........................ 6
2.6 Known Legitimate Therapeutic Uses for Tramadol ................................................ 7
2.7 Legitimate Distribution of Tramadol in New Zealand.............................................. 7
3.0 REGULATION/CLASSIFICATION ............................................................................. 8
3.1 The Current Regulation/Classification of Tramadol in New Zealand ...................... 8
3.2 The Experiences and Regulation/Classification of Tramadol Internationally .......... 8
3.3 The UN Classification of Tramadol ...................................................................... 10
4.0 RISK OF HARM IN NEW ZEALAND ....................................................................... 11
4.1 What are the Pharmacological, Psychoactive and Toxicological Effects of
Tramadol? ......................................................................................................... 11
4.2 Tramadol’s Abuse Appeal in Vulnerable Populations of New Zealand ................. 13
4.3 Tramadol’s Potential to Create Physical or Psychological Dependence............... 14
4.4 Tramadol’s Potential to Cause Death .................................................................. 16
4.5 Tramadol’s Potential for Diversion from Legitimate Sources................................ 17
4.6 Tramadol’s Seizures by Police, Customs and Medsafe ....................................... 17
4.7 Known Prevalence of Tramadol Abuse (including Misuse from Licit
Prescription and from Diversion)........................................................................ 17
4.8 Patterns of Abuse of Tramadol by Age, Gender, Ethnicity, Geography or
other Categorisation .......................................................................................... 17
4.9 Is Tramadol Use Identified as a Causal Factor for Presentations at Treatment
Facilities (including Hospitals, Rehabilitation and Addiction Centres)?............... 18
4.10 How many Hospital Admissions are Known to have been Caused by
Tramadol in the Last 2 years?............................................................................ 18
4.11 Are any Particular Sectors of the Population more Susceptible to Risk of
Harm Posed by the Abuse of Tramadol? ........................................................... 18
4.12 Public Health Risks Posed by the Abuse of Tramadol ....................................... 18
4.13 Other Risks of Harm to Society Posed by Abuse of Tramadol ........................... 18
5.0 ANTICIPATED FUTURE TRENDS.......................................................................... 19
6.0 OTHER RELEVANT INFORMATION ...................................................................... 19
7.0 CONCLUSION ........................................................................................................ 19
8.0 REFERENCE MATERIAL........................................................................................ 20
8.1 What Information Gaps Exist in Relation to Tramadol?........................................ 20
8.2 What Reference Material and Studies are Relevant to Tramadol in
New Zealand?.................................................................................................... 20
Page 2 of 22GLOSSARY
Analgesic: a drug or medicine given to reduce pain without resulting in loss of
consciousness, is any member of the diverse group of drugs used to relieve pain
Antagonist: (partial and full): a drug interacts with the receptor site and blocks or
depresses the normal response for that receptor; it may also prevent any other
agonist or the normal neurotransmitter from interacting with the receptor site
Antinociception: a reduction in pain sensitivity produced within neurons when an
endorphin or similar opium-containing substance opioid combines with a receptor
Endogenous: endogenous substances are those that originate from within an
organism
IDU: intravenous drug use or intravenous drug user. An IDU in New Zealand is
likely to be a poly-drug user, in that they will use more than one drug substance
during a session or over a period of time. People may combine drugs for an effect
or sometimes out of habit
Racemic mixture: or racemate in chemistry is one that has equal amounts of left
and right-handed enantiomers of a chiral molecule. A racemate is optically
inactive, because the two isomers rotate plane-polarised light in opposite
directions they cancel out, therefore a racemic mixture does not rotate plane-
polarized light. Enantiomers of a drug substance are likely to have different
potencies.
Somnolence: (or "drowsiness") is a state of near-sleep, a strong desire for sleep,
or sleeping for unusually long periods.
Page 3 of 221.0 INTRODUCTION
Tramadol is a prescription only medicine in New Zealand; while it is an opioid
type analgesic it is not currently classified as a controlled drug.
The abuse potential of this product is not reported to be analogous to other opioid
type analgesics; this is primarily because tramadol acts through several different
mechanisms including the µ-opioid receptor, serotonin and noradrenaline uptake
mechanisms.
International experience with tramadol suggests that this product is not highly
addictive; however, contrary to this, the US requires product labelling detailing the
potential for abuse and dependence. Several prominent health authorities,
including WHO, FDA, MHRA and the TGA, have considered tramadol for
reclassification however none have reclassified from a prescription medicine
status.
There is debate over the addictive nature of tramadol. It has been suggested that
abuse and dependence potential of tramadol is more severe in individuals that
have been, or are currently dependent upon opioid type drugs.
Page 4 of 222.0 SUBSTANCE IDENTIFICATION
2.1 The Chemical Name/Trade Names for Tramadol
Numerous pharmaceutical products containing tramadol have been registered
with Medsafe. Four companies within New Zealand market these. The tramadol
pharmaceutical products and their manufacturers include:
• AFT Pharmaceuticals Limited market Tramadol® capsules 50 mg.
www.medsafe.govt.nz/profs/datasheet/t/TramadolHydrochloridecap.htm
• CSL Biotherapies (NZ) Limited market five tramadol products containing
varying concentrations of tramadol;
! Tramal® capsules 50 mg,
! Tramal® solution for injection in concentrations 50 mg/mL and 100
mg/2mL,
! Tramal® SR sustained release tablets in four concentrations 50 mg, 100
mg, 150 mg and 200 mg,
! Tramal® retard modified release capsules in three concentrations 100
mg, 150 mg and 200 mg,
! Tramal® oral drops solution at 100 mg/mL.
www.medsafe.govt.nz/profs/datasheet/t/TramalcapSRtabinjoraldrops.htm
• Pacific Pharmaceuticals Limited (part of Mylan) market Tramedo capsules
50 mg. www.medsafe.govt.nz/profs/datasheet/t/Tramedocap.htm
• Mundipharma New Zealand Ltd market two modified release tramadol
products containing varying concentrations of tramadol:
! Zytram® BD modified release tablets in four concentrations 75 mg, 100
mg, 150 mg and 200 mg;
! Zytram® XL modified release tablets in four concentrations 150 mg, 200
mg, 300 mg and 400 mg.
Internationally tramadol finished product trade names include: Crispin®;
Dromadol®; Ralivia® ER; Ralivia® Flashtab; Tramake Insts®Tramadol
hydrochloride (HCl); Tramadolum [latin]; Tramal®; Tramodol HCl; Ultram®;
Zamadol® and Zydol®.
2.2 The Origin and History of Tramadol
Tramadol is a synthetic opioid analogue of codeine and was first synthesised in
1962 by Grünenthal Germany in an attempt to reduce common opioid adverse
effects such as respiratory depression. Grünenthal introduced Tramal® to the
market place in 1977.
Grünenthal state that tramadol is available in 100 countries worldwide, there have
been 100 million patients treated with more than 5.6 billion patient treatment days
associated to this treatment. www.tramal.com/tra/en_en/html/tramal_01a.jhtml
Tramadol was first approved in New Zealand in 1997.
Page 5 of 222.3 The Chemical Makeup of the Active Components: Tramadol
TRAMADOL
(±)-(trans/cis) 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexan-1-ol
[hydrochloride]
Tramadol hydrochloride is a white, crystalline powder, freely soluble in water and
in methyl alcohol, and very slightly soluble in acetone. It should be protected from
light (Martindale; 2007).
Tramadol is administered as a mixture of two stereoisomers (enantiomers) to
form the racemate.
2.4 Tramadol’s Similarity to Other Known Substances
Tramadol is a centrally-acting synthetic analgesic of the aminocyclohexanol
group. Although tramadol is a synthetic analogue of codeine, it has a significantly
lower affinity for opioid receptors than codeine. Additionally tramadol also
influences the activity of noradrenaline and serotonin processes in the central
nervous system.
Tramadol exists as a racemic mixture of the trans and cis isomer, with important
differences in binding, activity, and metabolism associated with the two
enantiomers.
2.5 Consumption and Administration of Tramadol (Licit and Illicit Use)
Tramadol is legitimately prescribed and administered to patients for the relief of
moderate to severe pain. It may be taken orally or administered as an
intramuscular or intravenous injection.
Tramadol, in the illicit setting, is likely to be taken as an oral dose, or dissolved
and injected. Tramadol is freely soluble in water.
Page 6 of 222.6 Known Legitimate Therapeutic Uses for Tramadol
Tramadol is employed in the clinical setting for the treatment of moderate to
severe pain; as such tramadol sits with codeine and di-hydro-codeine in the WHO
analgesic ladder.
Tramadol has been used to treat postoperative, dental, cancer, and acute
musculosketetal pain and as an adjuvant to NSAID therapy in patients with
osteoarthritis. It is widely prescribed by general practitioners (GP) and
increasingly so by emergency departments (ED). It appears that GP and ED
prescribers are unaware of the potential for tramadol to cause dependence (Dr
Tom Flewett).
Tamaskar et al 2003 and others suggest that tramadol is efficacious in the
treatment of opioid dependence; tramadol may be comparable to buprenorphine
in the management of mild to moderate heroin withdrawal. However, Grünenthal
state in their product monograph that tramadol is not suitable as a substitute in
opioid-dependent patients. Although it is an opioid agonist, Grünenthal confirm
that tramadol cannot suppress morphine withdrawal symptoms.
2.7 Legitimate Distribution of Tramadol in New Zealand
Tramadol is available in New Zealand only on prescription from a prescribing
physician.
Tramadol is planned to be, but is not yet a PHARMAC scheduled product, other
than that which is available for hospital use. Section H of the Pharmaceutical
Schedule lists pharmaceuticals that District Health Boards fund from their own
budgets. The Hospital Supply Status of tramadol products (cumulative to
November 2007), include the following tramadol products:
• Tramal capsule 50 mg;
• Tramal Retard sustained release tablet in the strengths 100 mg, 150 mg &
200 mg;
• Tramal Injection 50 mg per ml (1 mL & 2 mL).
De Cono et al 2005 suggests that the trend in sales of codeine, tramadol, fentanyl
and morphine in European countries has changed significantly; where tramadol
use has increased significantly compared to morphine. This is suggestive of
possible trends within New Zealand and a likelihood that tramadol may soon be a
PHARMAC scheduled and funded drug product, as a result of international
preference and best practice approaches to analgesia.
Page 7 of 223.0 REGULATION/CLASSIFICATION
3.1 The Current Regulation/Classification of Tramadol in New Zealand
Tramadol is a prescription only medicine in accordance with the Medicines Act
1981.
3.2 The Experiences and Regulation/Classification of Tramadol
Internationally
International
The WHO Expert Committee on Drug Dependence (ECDD) stated in 2003 that
tramadol and one of its metabolites are potent mu-opioid receptor agonists and its
pattern of abuse is similar to that of opioids by opioid abusers. The likelihood of
abuse of tramadol appears to vary between countries, depending on the
prevalence of opioid dependence, types of marketing strategy and other factors.
The information available to the ECDD Committee in 2003 was not sufficient for
the Committee to recommend international control of tramadol. But was adequate
to recommend that WHO keep the drug under surveillance.
http://whqlibdoc.who.int/trs/WHO_TRS_915.pdf
The INCB (International Narcotics Control Board) has not scheduled this drug
product. Tramadol is not listed under the United Nations Single Convention on
Narcotic Drugs 1961 or the Convention on Psychotropic Substances 1971.
Germany
Tramadol, under the brand name Tramal®, has been marketed by Grünenthal in
Germany, without controls, since 1977. It is reported to be one of the most widely
prescribed analgesics. It is a prescription only medicine in Germany.
There is little other information available on the German situation.
Australia
Tramadol is classified in Schedule 4 of the National Drug and Poisons Schedule,
making tramadol a Prescription Only Medicine in Australia. Schedule 4 drugs are
cited as substances and preparations for therapeutic use.
The Standard for the Uniform Scheduling of Drugs and Poisons is produced by
the National Drugs and Posions Schedualling Committee (NDPSC), a committee
of the Therpeutic Goods Administration (TGA). The NDPSC do not consider
tramadol to have significant dependence potential and hence have not
recommeded this substance for classification under Schedule 8.
Additionally the NDPSC noted that the WHO expert Committee on Drug
Dependence had reviewed tramadol in 1993 and 'on the basis of its low abuse
liability tramadol was not recommended by the Committee for critical review'. The
Page 8 of 22Committee agreed that a Schedule 4 classification was appropriate, and based
on its sedative effect, inclusion in Appendix K was also appropriate.
Canada
A recent paper published by Health Canada (2007) suggests that tramadol should
be considered for scheduling as a controlled drug, under Schedule I of the
Controlled Drugs and Substances Act (CDSA) and into the Schedule of the
Narcotic Control Regulations (NCR).
http://canadagazette.gc.ca/partI/2007/20070707/html/regle1-e.html
It is currently unclear what the classification of tramadol is in Canada.
USA
The US are purported to be amongst the highest users of prescription medicines
world wide, specifically narcotic type drugs. Diversion, misuse and abuse of these
pharmaceutical drugs are reported to be extremely significant.
The US Food and Drug Administration (FDA) has not recommended the
scheduling of this substance in the Controlled Substances Act (CSA). The US
DEA do not highlight this drug substance within their 2007 overview of narcotic
drugs.
However the manufacturer of Ultram® has been required to inform physicians
about recent abuse data. Ultram® product labelling now includes new information
under the "Drug Abuse and Dependence" section as follows:
"ULTRAM may induce psychic and physical dependence of the morphine-
type (µ-opioid). Dependence and abuse, including drug-seeking behaviour
and taking illicit actions to obtain the drug are not limited to those patients
with prior history of opioid dependence. The risk in patients with substance
abuse has been observed to be higher. ULTRAM is associated with craving
and tolerance development. Withdrawal symptoms may occur if ULTRAM is
discontinued abruptly."
A US federal database, for seized drugs analysed by the DEA forensic
laboratories, highlights 23 tramadol drug items from 11 different cases in 2006.
These items included 239 tablets and 9.17 grams of powder. The National
Forensic Laboratory System (NFLIS), state and local forensic laboratories
analysed 4,785 exhibits of tramadol in 2006. (DEA 2006)
Voluntarily submitted adverse events, to the FDA, from the time of initial
marketing in 1995 through September 2004, indicate 766 case reports of
tramadol abuse and 482 cases of withdrawal associated with tramadol. The DEA
confirm from these reports that narcotic addicts, chronic pain patients, and health
professionals most commonly abused tramadol. (DEA 2007)
Page 9 of 22Europe
The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) does
not provide an independent report on the status of tramadol.
www.emcdda.europa.eu
De Cono et al 2005 suggests that the trend in sales of codeine, tramadol, fentanyl
and morphine in European countries has changed significantly. European
purchases of fentanyl and tramadol increased considerably during the period
2001 – 2003 compared to morphine. During this time the total expenditure of
fentanyl reached that of tramadol; this was closely followed by codeine.
There is little available information on the current situation in specific European
countries including Germany, France, Spain, England or the Baltic region. The
German situation should be reviewed extensively, as Grünenthal (the German
innovator company) have been marketing tramadol since 1977 and report it to be
a widely prescribed analgesic.
3.3 The UN Classification of Tramadol
Tramadol is not listed within the United Nations Single Convention on Narcotic
Drugs 1961 or the Convention on Psychotropic Substances 1971, therefore there
is no international obligation to classify this drug substance.
Page 10 of 224.0 RISK OF HARM IN NEW ZEALAND
The illicit availability, use and risk of harm associated with tramadol are largely
dependent upon the therapeutic use or preference to the use of tramadol by the
prescribing physician.
4.1 What are the Pharmacological, Psychoactive and Toxicological Effects
of Tramadol?
Opioid Drugs
Opioid receptors are found throughout the brain and spinal cord, in the
gastrointestinal system, parts of the autonomic nervous system and on white
cells. This means opioid drugs have a wide range of actions on many organ
systems. The most prominent effects are exerted on the central nervous system
and the gastrointestinal tract.
Mu (µ) opioid receptors, the effector sites of much of tramadol’s action, are
involved in systems that influence mood, reinforcing behaviours, respiration, pain,
blood pressure and endocrine and gastrointestinal function (Jaffe 1992 from the
Ministry of Health, 2006).
Tramadol also has significant action on the re-uptake of serotonin and
noradrenaline within the central nervous system; the brain. Tramadol is
essentially a pro-drug and therefore requires to be metabolised before active
analgesic properties are apparent. The analgesic properties of tramadol can
additionally be attributed to norepinephrine and serotonin reuptake blockade in
the CNS, which inhibits pain transmission in the spinal cord. These actions impact
on the physiological response by the brain tissue and therefore may influence or
reinforce the drug taking behaviour or properties of the brain.
Pharmacology
Indication
Indicated in the treatment of moderate to severe pain.
Pharmacodynamics
Although pre-clinical testing has not completely explained the mode of action, at
least two complementary mechanisms appear applicable: binding to µ-opioid
receptors and inhibition of re-uptake of noradrenaline and serotonin.
µ-opioid receptors:
• The opioid-like activity of tramadol derives from low affinity binding of the
parent compound to µ-opioid receptors and higher affinity binding of the
principal active metabolite, O-desmethyltramadol, denoted M1, to µ-opioid
receptors. Tramadol and its O-desmethyl metabolite (M1) are selective, weak
µ-opioid receptor agonists. In animal models, M1 is up to 6 times more potent
than tramadol in producing analgesia and 200 times more potent in µ-opioid
Page 11 of 22binding. The contribution to human analgesia of tramadol relative to M1 is
unknown, but likely to be similar to animal models.
Noradrenaline and Serotonin:
• Tramadol inhibition of the re-uptake of noradrenaline and serotonin, similar to
other opioid analgesics, may contribute independently to the overall
analgesic profile of tramadol.
Analgesia:
• The analgesic effect is dose-dependant, but the relationship between serum
concentrations and analgesic effect varies considerably between individuals.
In one study, the median serum concentration of tramadol required for
effective post-operative analgesia was 300 ng/mL, with individual values
ranging from 20 to 990 ng/mL. The duration of the analgesic effect after a
single oral dose of tramadol 100mg is about 6 hours. Adverse effects,
nausea in particular, are dose-dependent and therefore considerably more
likely to appear if the loading dose is high.
• Apart from analgesia, tramadol may produce other symptoms similar to that
of opioids including: dizziness, somnolence, nausea, constipation, sweating
and pruritus (dermatological). However, tramadol causes significantly less
respiratory depression than morphine. In contrast to morphine, tramadol has
not been shown to cause histamine release. At therapeutic doses, tramadol
has no clinically significant effect on heart rate, left ventricular function or
cardiac index (vasodynamic parameter for heart performance= cardiac
output: body surface area). Orthostatic changes in blood pressure (postural
hypotension) have been observed.
• Both animal and human studies have shown that antinociception induced by
tramadol is only partially antagonised by the opiate antagonist naloxone
(Grünenthal, 2006). This may reinforce the notion of analgesic properties
associated to the serotonin and noradrenaline functions of tramadol.
Pharmacokinetics:
• Racemic tramadol is rapidly and almost completely absorbed after oral
administration. The mean absolute bioavailability of a 100 mg oral dose is
approximately 75%. The mean peak plasma concentration of racemic
tramadol and M1 occurs at two and three hours, respectively, after
administration in healthy adults.
• Tramadol is extensively metabolised after oral administration. The major
metabolic pathways appear to be N - and O -demethylation and
glucuronidation or sulfation in the liver. Only O -desmethyltramadol (M1) has
significant pharmacological activity (as above). Inhibition of one or both types
of the isoenzymes (CYP2D6) involved in the bio-transformation of tramadol
may affect the plasma concentration of tramadol or its active metabolite.
Page 12 of 22Toxicity:
• The risk of epileptic convulsions is increased when tramadol is given to
patients with a history of epilepsy. Tramadol toxicity has been associated to
concomitant use of digoxin. The sedative effects of benzodiazepines are
increased with dual administration of tramadol. There is an increased risk of
CNS toxicity when tramadol is given with an SSRI or TCA.
• Tramadol interacts with several drugs, including CNS depressants,
monoamine oxidase (MAO) inhibitors, selective serotonin re-uptake inhibitors
(SSRI’s), anti-psychotics, cardiac glycosides (digoxin), warfarin, and other
drugs that interact with the CYP2D6 isoenzyme.
For more detail to the above please refer to:
• Drug Bank -
http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-
bin/getCard.cgi?CARD=APRD00028.txt
• Medsafe tramadol datasheets -
www.medsafe.govt.nz/profs/datasheet/t/TramalcapSRtabinjoraldrops.htm
• Grünenthal GmbH Tramal® datasheet 2006 -
www.tramal.com/tra/en_en/pdf/prescribing.pdf
4.2 Tramadol’s Abuse Appeal in Vulnerable Populations of New Zealand
Grünenthal state that even when taken according to instructions, tramadol may
cause effects such as somnolence and dizziness. This applies particularly in
conjunction with other psychotropic substances, specifically alcohol (Grünenthal,
2006).
Anecdotal evidence suggests that tramadol creates a lull and a sense of euphoric
release from immediate worries.
One could therefore suggest that tramadol would be likened to other opioid drugs,
when used illicity and perhaps these drug actions described above would be
considered slightly favourable or appealling, especially in light of possible
reduced supply of other drugs of choice.
Counter to this, it could be surmised that the likely exposure to tramadol is
suppressed in addiction communities that have secured access to preferred,
more potent and euphoriant opioids than tramadol.
According to Skipper et al 2004 tramadol is a drug that is relatively frequently
abused by physicians (Alabama and Michigan), although it was rarely the primary
drug of choice. The finding that tramadol was mentioned more frequently than
fentanyl and oxycodone and other known highly addictive opioids could be
explained by an intrinsic abuse liability that was higher than previously thought. Of
the physicians that mentioned tramadol, the majority had a diagnosis of
substance dependence. The frequency of tramadol abuse was classified as
primary tramadol abuse (24%), relapse associated with tramadol use (42%) and
Page 13 of 22substitution of tramadol for the drug of choice (30%). It is likely that tramadol’s
prescription drug status (as opposed to "controlled") plays a role in its overall
misuse.
4.3 Tramadol’s Potential to Create Physical or Psychological Dependence
There are a number of issues relating to dependence. These include tolerance to
narcotic drug substances, increasing doses and dose escalation, the dependence
potential of the drug of choice, poly-drug use, and issues with withdrawal and
progression to other drug substances of abuse specifically when the supply of
that that drug of choice becomes unavailable.
Tramadol does not necessarily produce significant euphoriant effects, like
morphine, heroin or oxycodone. However, the withdrawal effects of tramadol use
are noted to be similar to those of opioid withdrawal and include a degree of
craving.
Adams et al their paper titled A Comparison of the Abuse Liability of Tramadol,
NSAIDs, and Hydrocodone in Patients with Chronic Pain explain that behaviors
suggestive of addiction/dependence include an inability to take medications
according to an agreed upon regimen (schedule), taking multiple doses together,
isolation from family and friends, use of analgesic medications for other than
analgesic effects such as sedation, anxiety, or intoxication.
The hypothesis underlying this study was that abuse/dependence associated with
tramadol would not be higher than the negative control (NSAIDs) and would be
lower than the positive control (hydrocodone-containing analgesics). The sample
population included patients with non-cancer type pain, the majority of which were
women. The results support the hypothesis that the rate of abuse identified with
tramadol is not significantly greater than NSAIDs, but is less than the rate
associated with hydrocodone. Furthermore, abuse/dependence in this population
was low overall and consistent with other studies of large patient populations.
Importantly, the rate was also relatively low among chronic pain patients with a
history of drug abuse. (Adam et al, 2006). Although the study sample was large,
this population did not align to the typical characteristics of an individual with drug
abuse issues, such as an IDU.
Grünenthal:
• Grünenthal’s medicine datasheet recommends that tramadol may only be
used with particular caution in opioid-dependent patients and that tramadol
has a low dependence potential. On long-term use tolerance, psychic and
physical dependence may develop. In patients with a tendency to drug abuse
or dependence, treatment with tramadol should only be carried out for short
periods under strict medical supervision. Tramadol is not suitable as a
substitute in opioid-dependent patients. Although it is an opioid agonist,
tramadol cannot suppress morphine withdrawal symptoms; this statement is
contrary to what has otherwise been recently reported (Grünenthal 2006)
Page 14 of 22Beijing, China:
• A Chinese study, conducted by the National Institute on Drug Dependence,
Beijing, enlisted 219 subjects categorised as opiate addicts with history of
tramadol abuse. Study subjects were assessed using an opiate withdrawal
scale. The results indicate that tramadol resulted in euphoric effects, sedative
effects, and psychotomimetic effects. 57.1% of tramadol abuse subjects had
a craving for tramadol. The National Institute on Drug Dependence, Beijing,
conclude that tramadol produced high abuse potential among opiate addicts.
Martindale:
• Tramadol may have lower potential for producing dependence than
morphine. The UK Committee on Safety of Medicines of the (CSM-MHRA)
commented in October 1996 that since June 1994 they had received reports
of drug dependence in 5 patients and withdrawal symptoms associated with
tramadol in 28 patients, which corresponded to a reporting rate of about 1 in
6000 (Martindale, 2007).
• Doses in excess of the recommended maximum of 400 mg daily had been
taken by 5 of the patients. The duration of treatment before onset of these
effects ranged from 10 to 409 days (average 3 months). Withdrawal
symptoms reported were typically those of opioid withdrawal in general.
www.medicinescomplete.com/mc/martindale/current/6263-
c.htm?q=%22tramadol%22#m6263-a3-2-s-1
Conclusions:
• Some controversy obviously exists regarding the dependence liability of
tramadol. Grünenthal has promoted it as an opioid with a lower risk of opioid
dependance than that of traditional opioids, claiming little evidence of
dependence in clinical trials. Grünenthal suggest that since the M1
metabolite is the principal agonist at the µ-opioid receptor, the delayed
agonist activity reduces dependence liability. Grünenthal mean that tramadol
drug subsatnce is required to be metabolised within the liver before an acitve
metabolite is formed. It is also likely that the noradrenaline and serotonin
reuptake mechansiums play some role in dependence.
• Dependence liability has been considered by several relevant authorities,
including the UN INCB, TGA, FDA, Health Canada and the WHO as being
relatively low. Nevertheless, the prescribing information in the US for
Ultram® warns that tramadol "may induce psychological and physical
dependence of the morphine-type".
• Based upon the evidence presented above one could argue that there is
some significant abuse potential in those that already use opiates, have a
history of addiction or are currently addicted to the use of opiate type drug
substances.
Page 15 of 224.4 Tramadol’s Potential to Cause Death
In principle, on intoxication with tramadol, symptoms similar to those of other
centrally acting analgesics (opioids) are to be expected. These include in
particular miosis (contraction of the pupil), vomiting, cardiovascular collapse,
consciousness disorders up to coma, convulsions and respiratory depression up
to respiratory arrest (Grünenthal, 2006). Tramadol, like most low-level analgesics
is available in combination with paracetamol; this raises greater concerns in
overdose due to liver toxicity from paracetamol.
Pre-clinical data indicates that central nervous manifestations only occurred after
high doses considerably above the therapeutic range (excessive single oral
doses (700 mg) or large intravenous doses (300 mg)). Central nervous symptoms
include restlessness, salivation, convulsions, and reduced weight gain
(Grünenthal, 2006).
The risk of an adverse outcome from the use of tramadol is increased in the
following concomitant conditions or concomitant drug use:
• individuals with known hypersensitivity to tramadol;
• acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic
drugs;
• patients who are taking MAO inhibitors or who have taken them within the
last 14 days;
• known hypersensitivity to opioids;
• patients with uncontrolled epilepsy or epilepsy not adequately controlled by
treatment;
• warfarin.
International case reports provide evidence of an interaction between oral
tramadol and warfarin in some individuals, leading to an elevated International
Normalised Ratio (INR) and in some instances bruising or haemorrhage. The
mechanism has not been determined (Medsafe 2006).
Tramadol use is known to be associated with a condition described as the
serotonin syndrome. This is particularly so at high doses or when given with other
drugs that raise serotonin concentrations, or there is concomitant use of
medicines that lower the seizure threshold (Martindale 2007, Medsafe 2007).
Martindale states that the UK CSM commented that since June 1994 they had
received reports of 15 patients who had experienced confusion and/or
hallucinations while taking tramadol. The majority of the reactions developed 1 to
7 days after starting treatment and in most patients resolved rapidly on
withdrawal. It was noted that psychiatric reactions comprised about 10% of all
reactions reported with tramadol (Martindale 2007).
In a later comment in October 1996, the CSM received 27 reports of convulsions
and one of worsening epilepsy, this corresponds to a reporting rate of about 1 in
Page 16 of 227000. Of the 5 patients receiving intravenous tramadol, 2 had been given doses
well in excess of those recommended. Of the patients receiving oral tramadol, the
majority were taking other drugs known to cause convulsions, including tricyclic
antidepressants and SSRIs. A similar pattern has been reported in the USA and
Australia (Martindale 2007).
4.5 Tramadol’s Potential for Diversion from Legitimate Sources
As with all drug substances of this kind, especially those that do not hold a
controlled drug status, the possibility for diversion is significant. The abuse
potential of a drug product such as tramadol would suggest that it is not a drug of
preference, but is potent enough to generate a certain level of diversion.
Tramadol not being scheduled as a Controlled Drug could make it more attractive
as a drug of abuse.
4.6 Tramadol’s Seizures by Police, Customs and Medsafe
In the previous 2 years Customs has posted 30 information reports that include
the drug substance tramadol. These information reports include tramadol brand
names or have been identified as Tramadol®, Tramal® and Crispin®; 10, 6 and
14 Customs information reports are associated to these brands, respectively.
Crispin® is not a registered tramadol brand name in New Zealand; it is unclear
the country of origin of this generic product, it is possibly sourced from Europe.
There have been no reported police seizures or arrests associated with this drug
substance.
4.7 Known Prevalence of Tramadol Abuse (including Misuse from Licit
Prescription and from Diversion)
This data is difficult to establish.
The needle exchange and specialist AOD clinics do not report the abuse, misuse
or injection of tramadol (at least not notably). It is likely that diversion, abuse or
misuse of tramadol would be less than other more effective euphoric drugs such
as diverted oxycodone, methadone or other strong opioid drugs including opium.
4.8 Patterns of Abuse of Tramadol by Age, Gender, Ethnicity, Geography or
other Categorisation
This data is difficult to establish.
Page 17 of 224.9 Is Tramadol Use Identified as a Causal Factor for Presentations at
Treatment Facilities (including Hospitals, Rehabilitation and Addiction
Centres)?
There are likely to have been few admissions to drug treatment services in New
Zealand by individuals that have a history of abuse of tramadol or are currently
abusing this substance.
A Wellington drug treatment clinic highlighted that one European patient had
been admitted to the clinic due to their abuse of tramadol as a primary substance,
and that this was due to that patient being an emigrant from a country in which
tramadol is widely available.
4.10 How many Hospital Admissions are Known to have been Caused by
Tramadol in the Last 2 years?
This information is unknown due to limitations in the hospital admissions dataset.
4.11 Are any Particular Sectors of the Population more Susceptible to Risk
of Harm Posed by the Abuse of Tramadol?
The most at risk populations are the established opioid using IDU and those that
misuse tramadol when taking concomitant medicines that interact with tramadol.
The IDU that are more at risk include IDU that are new to injecting drugs; those
IDU that have had the supply of alternative drugs or their drug of choice
discontinued or ceased; and those drug users that are experimenting with
injecting or other types of drug use.
4.12 Public Health Risks Posed by the Abuse of Tramadol
Tramadol appears to be a relatively safe drug substance even when misused and
abused, this is especially so when considered in comparison to other more potent
opioid type drug substances.
If tramadol was to be injected then the overall public health risk associated to the
misuse and abuse of tramadol is considerable. As with all drugs of abuse that are
injected there are significant issues relating to overall health (psychological and
physical) of the individual and the effect this activity has on their community. The
risk of contacting or transmitting a blood-borne viral disease (e.g. HIV, HCV) is
significantly increased with the intravenous use of a drug substance.
4.13 Other Risks of Harm to Society Posed by Abuse of Tramadol
The overarching cost to society from pharmaceutical diversion of products used
as a legitimate treatment for pain. This is regardless of whether it is a drug
product that is partially funded or fully-funded by PHARMAC.
Page 18 of 225.0 ANTICIPATED FUTURE TRENDS
There appears to be a ready supply of other alternative, and more potent, opioid
type drugs available to the market, both legitimately and illicitly.
Due to the limited availability of tramadol, compared to these other opioid type
drugs, in New Zealand and in the absence of any change to the scheduling of
tramadol by PHARMAC, it is not anticipated that there will be any significant
changes from the current situation during the coming years.
6.0 OTHER RELEVANT INFORMATION
It would have been useful to have had data to establish:
• the price of tramadol on the black market;
• its availability;
• its preference of choice over other opioid and other intravenous drugs; and
• the extent to which the availability of these other drugs influence the choice
to use tramadol.
7.0 CONCLUSION
Although the misuse of tramadol does not appear to be significant in New
Zealand, relevant research indicates that tramadol has some significant abuse
potential, especially with patients/individuals with a history of opioid
use/abuse/misuse.
Recommendations:
• One option is that tramadol remains as a prescription only medicine, but that
prescribers of this medicine are made more aware of this drugs potential to
cause dependence and its capability to be misused and abused.
• Alternatively, it is likely tramadol will be partially or fully funded by
PHARMAC, and as a result its availability may increase; then perhaps
tramadol should be classified in Schedule III, as a Class C (2) drug
substance; inline with codeine and propoxyphene.
Page 19 of 228.0 REFERENCE MATERIAL
8.1 What Information Gaps Exist in Relation to Tramadol?
There are no recorded cases of Police seizures of tramadol. It is possible that
this is due to under reporting, or more likely as a result of tramadol not being a
controlled drug.
Due to limitations in the hospital admissions dataset there is no data available on
hospital admissions caused by tramadol.
The price of tramadol on the black market, availability, preference of choice over
other opioid and other intravenously used drugs and the extent to which the
availability of these other drugs influence the choice to use tramadol are
questions that could be further examined.
The German situation should be reviewed extensively, as Grünenthal a German
pharmaceutical company have been marketing tramadol since 1977 and report its
use to be high. Currently there is little data available on tramadol from Germany.
8.2 What Reference Material and Studies are Relevant to Tramadol in New
Zealand?
Expert Opinion
Kate Coombe-McNaught, Head Nurse, Wellington Pain Clinic, Wellington
Hospital, Capital Coast District Health Board.
Dr Tom Flewett, Addiction Specialist, Community Alcohol and Drug Service,
Capital Coast District Health Board.
Dr Geoff Robinson, Chief Medical Officer Capital & Coast District Health Board.
Medsafe (Ministry of Health).
Ministry of Health Medicines Control Team.
Texts and Guidelines
British Medical Association and Royal Pharmaceutical Society of Great Britain.
British National Formulary, 54 ed. London. 2007.
Goodman and Gilman's The Pharmacological Basis of Therapeutics. McGraw
Hill. 2007.
Jaffe. Opiates: Clinical Aspects. Lowinson, Ruiz, Millman. Substance Abuse: A
Comprehensive Textbook (2nd Ed.). Baltimore: Williams and Wilkins. 1992.
Martindale: The Complete Drug Reference. Sweetman SC (Ed). Pharmaceutical
Press (London). 2007. www.medicinescomplete.com/mc/martindale/current/6263-
c.htm?q=%22tramadol%22#m6263-a3-2-s-1
Page 20 of 22Medsafe. Evidence For Tramadol-Warfarin Interaction. Prescriber Update;
27(2):23-24. 2006. www.medsafe.govt.nz/profs/puarticles/tramwarf.htm
Medsafe. Serious Reactions with Tramadol: Seizures and Serotonin Syndrome.
Prescriber Update;28(1):11-13. 2007.
www.medsafe.govt.nz/profs/puarticles/tramserious.htm
Journal Articles
Adams, Breiner, Cicero, Geller, Inciardi, Schnoll, Senay and Woody
A Comparison of the Abuse Liability of Tramadol, NSAIDs, and Hydrocodone
in Patients with Chronic Pain. Journal of Pain and Symptom Management 465, 31
(5), 2006.
http://paincenter.wustl.edu/c/BasicResearch/documents/CiceroJPain2006.pdf
Brinker; Renan; Bonnel & Beitz. Abuse, Dependence, or Withdrawal Associated
With Tramadol. American Journal of Psychiatry 159:881, May 2002.
Related articles: http://ajp.psychiatryonline.org/cgi/content/full/159/5/881
De Conno; Ripamonti & Brunelli. Opioid Purchases and Expenditure in Nine
Western European Countries: ‘Are We Killing Off Morphine?’ Palliative Medicine,
19(3), 179-184. 2005.
Health Canada. Order Amending Schedule I to the Controlled Drugs and
Substances Act. Statutory Authority, Controlled Drugs and Substances Act,
Sponsoring department, Department of Health, Canada. Vol. 141, No. 27 — July
7, 2007
Liu, Zhou, Lian, Mu, Ren, Cao & Cai. Drug Dependence and Abuse Potential of
Tramadol. National Institute on Drug Dependence, Beijing, China. Chung Kuo
Yao Li Hsueh Pao; 20(1):52-4. 1999 Jan. Refer to Zhao Chengzheng
(zhaocz@bjmu.edu.cn) from the National Institute on Drug Dependence, Beijing,
China.
Reith, Fountain and Tilyard. Opioid Poisoning Deaths in NZ (2001–2002).
New Zealand Medical Journal. 118 (1209): 1293–1301. 2005.
Skipper; Fletcher; Rocha-Judd & Brase. Tramadol Abuse and Dependence
Among Physicians. Journal of the American Medical Association.
292:1818-1819. 2004.
Tamaskar; Parran; Heggi; Brateanu & Rabb. Tramadol versus Buprenorphine for
the Treatment of Opiate Withdrawal: a Retrospective Cohort Control Study.
Journal of Addictive Diseases, 22 (4):5-12. 2003.
Yates; Nguyen; Warnock. Tramadol Dependence with no History of Substance
Abuse (letter). American Journal of Psychiatry, 158:964. 2001
Related articles: http://ajp.psychiatryonline.org/cgi/content/full/159/5/881
Page 21 of 22Online Information
Grünenthal GmbH Tramal® datasheet 2006.
www.tramal.com/tra/en_en/pdf/prescribing.pdf
Medsafe Tramadol Datasheets.
www.medsafe.govt.nz/profs/Datasheet/SearchResult.asp
National Drugs and Posions Schedualling Committee (NDPSC), Therpeutic
Goods Administration (TGA). www.tga.gov.au/ndpsc/index.htm
USA DEA, Office of Diversion Control. 2007. Drugs and Chemicals of Concern:
Tramadol Précis.
http://www.deadiversion.usdoj.gov/drugs_concern/tramadol.htm
WHO Expert Committee on Drug Dependence (ECDD), 2006. 34th ECDD
2006/4.5 Assessment of Tramadol.
www.who.int/medicines/areas/quality_safety/5.2TramadolCritReview.pdf
WHO Expert Committee on Drug Dependence (ECDD). Technical Report Series
(915), Thirty Third Report. Geneva 2003.
http://whqlibdoc.who.int/trs/WHO_TRS_915.pdf
Wishart et al (2006), Drug Bank: A Comprehensive Resource for In-Silico Drug
Discovery and Exploration. Nucleic Acids Res.
http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-
bin/getCard.cgi?CARD=APRD00670.txt
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