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TRAMADOL
Comments on the EML application
for inclusion of opioid analgesics for cancer pain: fentanyl, methadone, tramadol
21st WHO Expert Committee on the Selection and Use of Essential Medicines
Prepared and submitted by:
Grünenthal GmbH, Germany
for the World Health Organization
23 February 2017
Grünenthal
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
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CONTENT
LIST OF ABBREVIATIONS
2
1
EXECUTIVE SUMMARY
3
2
REGULATORY STATUS AND AVAILABILITY
4
3
3.1
3.2
3.3
PHARMACOTHERAPY
Pharmacology of tramadol
Treatment details
Guideline recommendations
5
5
5
7
4
4.1
4.2
4.3
PUBLIC HEALTH RELEVANCE
Disease burden
Tramadol’s place in therapy
Patient access
9
9
9
10
5
5.1
5.2
CLINICAL EFFICACY
Efficacy in cancer related pain
Efficacy in non-cancer pain
13
13
15
6
6.1
6.2
6.3
SAFETY AND TOXICITY
Adverse event profile and comparative safety vs traditional opioids
Abuse potential vs traditional opioids
Safety profile of potential alternatives in mild to moderate pain
16
16
17
18
7
REFERENCES
19
8
ANNEXES
26
LIST OF ABBREVIATIONS
Abbreviation
Explanation
CYP
Cytochrome P450
CYP2D6
Iso-enzyme 2D6 of CYP.
EML
WHO Model List of Essential Medicines
GRT CCDS
Grünenthal Core Company Data Sheet
IMS
Intercontinental Marketing Services
IR
Immediate release
PR
Prolonged release
PM
Poor metabolizer
WHO
World Health Organization
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Model List of Essential Medicines (EML) 2017
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EXECUTIVE SUMMARY
Tramadol is available in more than 100 countries (Grond and Sablotzky 2004). It has regulatory
approval for the treatment of moderate to severe pain (most countries) or for moderate to moderately
severe pain (USA). In Japan the approval explicitly includes the indication cancer pain. In a number
of countries tramadol is also registered for use in the pediatric population.
Tramadol single active products are patent free worldwide and marketing authorizations are held by
many companies. Tramadol is available as various oral and parenteral preparations.
Tramadol is a standard WHO step-2 analgesic that has been used in medical practice over 40 years,
with a cumulative patient exposure of more than 30 billion patient treatment days for tramadol
containing-products worldwide (IMS Health Kilochem data, 2015).
Tramadol differs from traditional opioids such as morphine or codeine (which is a pro-drug of
morphine) by its multiple mode of action, combining weak μ-opioid and non-opioid effects (Raffa et
al. 1992, Desmeules et al. 1996, Eggers and Power 1995, Stamer et al. 2003). As a result, tramadol is
effective both in nociceptive pain and neuropathic pain. In a recent guideline by IASP (Finnerup et
al. 2015), tramadol is recommended as a second-line agent (traditional opioids being third-line
agents) for the management of neuropathic pain. At equi-analgesic doses, tramadol shows less
constipation, fewer effects on the respiratory system and a lower abuse and dependence potential
than traditional opioids such as morphine (Grond and Sablotzki 2004). This profile makes it
especially useful for longer-term treatment of cancer (or non-cancer) pain, especially in the
outpatient setting.
Tramadol is listed as a step-2 analgesic in the WHO guidelines on Cancer Pain Relief (WHO 1996)
and in numerous national and supranational cancer pain guidelines or lists from learned societies.
The available literature supports the use of tramadol as an effective WHO step-2 analgesic in the
treatment of moderate to severe cancer pain in adults and children. Tramadol’s demonstrated efficacy
in nociceptive and neuropathic pain is of particular relevance for cancer pain which often includes
both types of pain. Its efficacy is similar to that of lower doses of strong opioids such as morphine.
Tramadol is also a viable alternative to (high dose) NSAIDs and COX-2 inhibitors in longer-term
treatment and in the elderly, given the use-limiting safety issues associated with NSAIDs
(gastrointestinal bleeding) or NSAIDs as well as COX-2 inhibitors (cardiovascular risks,
nephrotoxicity).
Tramadol plays a particularly important role in developing countries, where controlled opioid
analgesics are still barely available. 5.3 billion people (76% of the world population) live in countries
with low to non-existent access to controlled opioid analgesics (Duthey and Scholten 2014).
Tramadol is not internationally controlled and is available as a regular prescription medicine in most
countries worldwide. It comes with a range of formulations similar to those listed for the essential
medicine morphine. There are many situations where tramadol is the only option available for the
treatment of moderate to severe cancer pain, given that it is accessible to in- and outpatients also in
regions wherein controlled opioids are not accessible.
In conclusion: In light of these supportive elements, the inclusion of tramadol on the WHO Model
List of Essential Medicines is justified.
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Model List of Essential Medicines (EML) 2017
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REGULATORY STATUS AND AVAILABILITY
Tramadol was first registered in Germany in 1973. To date tramadol has marketing authorizations all
over the world, including regulatory approvals from the following national health authorities:
National Health Authorities of the European Union, Swissmedic (Switzerland), Food and Drug
Administration (FDA; United States), and the Pharmaceutical and Medicines Devices Agency
(PMDA; Japan).
Tramadol is registered for the treatment of moderate to severe pain (most countries) or for moderate
to moderately severe pain (USA). In Japan the indication is disease-specific and explicitly lists
cancer pain: tramadol parenteral formulations are authorized for cancer pain and postoperative pain;
tramadol single ingredient oral formulations are authorized for the relief of cancer pain (approval in
2010) and for chronic pain (approval in 2013) which cannot be managed with non-opioid analgesics.
In a number of countries tramadol is also registered for use in the pediatric population.
Authorized formulations include immediate-release capsules or tablets, oral solution, prolongedrelease tablets, solutions for parenteral use (iv, sc, im) and suppositories.
Tramadol in products containing no other active ingredients is patent free worldwide and as it is
generic, prices are on a low level.
Marketing authorizations for tramadol as a medicine are held by many companies. Examples are
Winthrop Pharmaceuticals, Zentiva, Actavis, Consilient Health, Bristol Laboratories Ltd, BMM
Pharma, Ethypharm SA, Sandoz, Pharmaceutical, Nippon Shinyaku Co, Beacon Pharmaceuticals,
Sanofi Aventis France, Actavis Elizabeth, Amneal Pharmaceuticals, Watson Labs, Caraco, Sandoz,
Asta, Teva, Pharma BV, Mylan Pharmaceuticals Inc, Apotex Inc, Pliva, Mallinckrodt, Mylan,
Northstar Healthcare, Sun Pharma Global, Anchen Pharms, Lupin Ltd, IPCA Labs Ltd, Meda
Pharma BV, Apotex Europe BV, Pharmachemie BV, Grünenthal GmbH, Gedeon, Richter Plc,
Janssen Pharmaceuticals.
Tramadol is not an internationally controlled substance. It is available as a regular prescription
medicine in most countries worldwide.
In Annex 1 we provide an overview of countries where tramadol is admitted to the market by various
companies. The information was obtained from IMS Health Kilochem data 2016 and lists countries
and formulations. This non-exhaustive overview shows that tramadol is broadly available in different
regions of the world, including many countries classified as low or middle income countries by the
International Monetary Fund (International Monetary Fund 2016). Tramadol pharmaceutical forms
most widely available are oral solid IR/ PR and parenteral formulations (almost all countries),
followed by oral liquid and rectal formulations.
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PHARMACOTHERAPY
3.1
Pharmacology of tramadol
Tramadol combines weak µ-opioid and non-opioid modes of action and thus differentiates itself from
traditional opioids such as morphine or codeine. Tramadol is a centrally acting analgesic with
selective affinity for the µ-opioid receptors which mediates its antinociceptive action. At the same
time it acts synergistically on the neuroamine transmission by inhibiting synaptic noradrenaline and
serotonin reuptake and inducing intrasynaptic serotonin release likely responsible for its observed
effects in neuropathic pain. Tramadol is converted via CYP2D6 to its active metabolite M1 with an
affinity to µ receptors that is higher than that of the parent compound but overall an order of
magnitude lower than that of morphine (Raffa et al. 1992, Gillen et al. 2000).
3.2
Treatment details
Diagnosis and monitoring
Diagnosis and monitoring of treatment with the centrally acting analgesic tramadol is carried out
according to general principles of analgesic treatment with opioids in acute and chronic pain.
Dosages and administration (based on GRT CCDS, vs 18)
The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient.
The lowest effective dose for analgesia should generally be selected. The total daily dose of 400 mg
tramadol hydrochloride (adults) should not be exceeded, except in special clinical circumstances.
- Adults and adolescents above the age of 12 years:
Solution for injection (50 mg/ml or 100mg/2ml) and Oral drops (100 mg/ml), Capsules (50 mg),
Tablets (50 mg), Suppositories (100 mg): 50-100 mg tramadol hydrochloride 4-6 hourly.
Prolonged release tablets (50 mg, 100 mg, 150 mg, 200 mg): 50 – 100 mg twice daily, morning
and evening. If pain relief is insufficient, the dose may be titrated upwards to 150 or 200 mg
twice daily.
- Children:
In a number of countries in Europe, Latin America and Asia, tramadol solution for injection and
oral drops are also registered for use in pediatric patients. Dosing recommendations based on
Grünenthal’s Core Company Data Sheet, vs.18 are as follows:
Solution for Injection (50 mg/ml or 100 mg/2ml), Oral drops (100 mg/ml): Above the age of 1
year single dose 1-2 mg/kg body weight. The total daily dose of 8 mg tramadol hydrochloride per
kg body weight or 400 mg tramadol hydrochloride, whichever is lower, should not be exceeded.
Capsules (50 mg), Tablets (50 mg), Suppositories (100 mg), Prolonged release tablets (50 mg,
100 mg, 150mg, 200mg): On account of their high dosage strengths, these formulations are not
intended for children below the age of 12 years.
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Model List of Essential Medicines (EML) 2017
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- Elderly patients (all formulations):
Dose adjustment is not usually necessary in patients up to 75 years without clinically manifest
hepatic or renal insufficiency. In patients over 75 years elimination might be prolonged.
Therefore, if necessary the dosage interval is to be extended according to patient´s requirements.
- Patients with renal insufficiency/dialysis and hepatic impairment:
In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these
patients prolongation of the dosage intervals should be carefully considered according to the
patients requirements. In cases of severe renal and/or severe hepatic insufficiency tramadol
prolonged-release tablets are not recommended.
Duration of administration
As for other analgesics, the duration of tramadol administration should be adapted to the nature of
the patient’s pain. If long-term pain treatment is necessary, careful and regular monitoring should be
carried out (if necessary with breaks in treatment) to establish whether and to what extend further
treatment is necessary.
Pharmacokinetics
The pharmacokinetics of tramadol is dose proportional (Grünenthal data on file). After a single oral
dose the absolute bio-availability of tramadol is 68% to 77% depending on formulation (Lintz W et
al. 1986, Lintz W et al. 2000). Time to peak serum concentration is about 2 hours. Upon repeated
oral doses, the absolute bio-availability is only negligibly different from 100%; steady-state is
reached within 30 hours to 36 hours (Grünenthal data on file).
Tramadol is mainly metabolized by CYP2D6 (O-desmethylation), CYP3A4 and CYP2B6 (Ndesmethylation, Subrahmanyam et al. 2001). Tramadol and its metabolites are almost exclusively
excreted via the kidneys. The plasma elimination half-lives of tramadol and M1 are 5-7 hours and
6-8 hours (Stahlberg et al. 1993).
Interactions
Tramadol has only very limited potential for impact on the pharmacokinetics of other medicines
(Klotz 2003). Upon concomitant or previous administration of cimetidine (enzyme inhibitor)
clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of
carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action
of tramadol. Substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might
inhibit the metabolism of tramadol (N-demethylation) and probably also the metabolism of the active
O-demethylated metabolite. The clinical importance of such an interaction has not been studied.
Concomitant administration of tramadol with other centrally depressant medicinal products including
alcohol may potentiate the CNS effects. Tramadol can induce convulsions and increase the potential
for other seizure threshold-lowering medicinal products to cause convulsions.
Tramadol should not be combined with MAO inhibitors (contraindication).
Concomitant therapeutic use of tramadol and serotonergic medicines may cause serotonin toxicity.
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3.3
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
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Guideline recommendations
Tramadol is listed as a step-2 analgesic in the WHO guidelines Cancer Pain Relief, 2nd Edition
(WHO 1996). It is also included in numerous national and supranational cancer pain guidelines or
lists from learned societies, for example:
- The International Association for Hospice & Palliative Care (IAHPC) list of essential medicines
2007 (De Lima et al. 2007)
- European Association for Palliative Care (EAPC) guidelines on the use of opioids for the
treatment of cancer pain (Caraceni et al. 2012)
- European Society for Medical Oncology (ESMO) Clinical Practice Guidelines: Management of
cancer pain (Ripamonti et al. 2012)
-
German Medical Association, Committee on Medicines: Cancer pain 2007, Germany
(Arzneimittelkommission der deutschen Ärzteschaft)
Accessible at: http://www.akdae.de/Arzneimitteltherapie/TE/A-Z/PDF_Kurzversion/Tumorschmerz_k.pdf
- German Society for the Study of Pain (DGGS): Short introduction into the therapy of cancer
pain, Germany (Wirz et al. 2011)
- Japanese guideline 'Clinical Guidelines for Cancer Pain Management', Japan
Accessible at: https://www.jspm.ne.jp/guidelines/pain/2014/pdf/pain2014.pdf
- Clinical Guidelines and Palliative Care AUGE about Pain Relief caused by Cancer, Chile
Accessible at: http://www.bibliotecaminsal.cl/wp/wp-content/uploads/2016/04/Alivio-del-Dolor-por-Cáncer-yCuidados-Paliativos.pdf
-
‘Manual de Rutas Clinicas de Dolor’, El Tunal Hospital, Colombia
Accessible at:
http://www.hospitaleltunal.gov.co/hostingtunal/joomla%203.x/legend_j3_quickstart/InformacionInstitucional/LIBR
O%20MANUAL%20RUTAS%20CLINICAS%20DE%20DOLOR%202015.pdf
- Pain and Cancer by ACED, Colombia
Accessible at: http://www.dolor.org.co/libro/Dolor%20y%20Cancer.pdf
- ‘Paliación y cáncer’, Colombia
Accessible at: http://cuidadospaliativos.org/uploads/2013/4/LIBRO%20PALIACION%20CANCER%20FIN
- Clinical Practice Guideline in Palliative Care – MSP, Ecuador
Accessible at:
http://instituciones.msp.gob.ec/documentos/Guias/guias%202014/GPC%20Cuidados%20paliativos%20completa.pdf
-
Technical Notification NTS No062 MINSA .DGSP-V01 Pain Management GPC Neuropathic
Pain in the patient with cancer – National Institute of oncological disease – INEN, Peru
Accessible at: http://bvs.minsa.gob.pe/local/MINSA/1456.pdf
-
Guideline of Clinical Practice in Palliative Care, México SSA
Accessible at:
http://www.cenetec.salud.gob.mx/descargas/gpc/CatalogoMaestro/445_GPC_Cuidados_paliativos/GER_Cuidados_
Paliativosx1x.pdf
Given the wide variety of conditions in which tramadol can relieve pain, tramadol is also included in
various national and international guidelines on acute and chronic pain management, e.g. in
neuropathic pain (e.g. Finnerup et al. 2015, Attal et al. 2010), acute and chronic low back pain (e.g.
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Model List of Essential Medicines (EML) 2017
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Chou et al. 2007), or osteoarthritic pain (e.g. Simon et al. 2002). Its position in pain management
worldwide is further reflected by the inclusion of tramadol in various ‘Lists of Essential Medicines’.
- Médecins Sans Frontière list of essential medicines (Pinel et al. 2013)
- International Maritime Organization: List of contents of the ‘emergency medical kit/bag’ and
medical consideration for its use on ro-ro passenger ships not normally carrying a medical doctor
(Schlaich et al. 2009)
- The Interagency Emergency Health Kit 2011: medicines and medical devices for 10 000 people
for approximately three months (WHO 2011)
- National Essential Medicines Lists (NEMLs): tramadol is included in about half of the NEMLs
accessible through the WHO website (Kamerman et al. 2015)
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4.1
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PUBLIC HEALTH RELEVANCE
Disease burden
In cancer, pain is one of the most feared and burdensome symptoms (van den Beuken-van
Everdingen et al. 2007).
However, despite advances in cancer care and pain management, many patients with cancer pain
obtain inadequate pain relief (Kongsgaard et al. 2009).
Cancer patients may suffer from pain not only in the last months of life, but also at the time of
diagnosis and during active treatment (Ripamonti et al. 2012). Increasing numbers of patients are
clear of cancer following treatment, but often experience chronic pain syndromes upon completion of
treatment. Others are not cured, but can remain in a chronic, stable disease state for many years
(Müller-Schwefe et al. 2014). Cancer related pain may be the result of the cancer itself, oncology
treatment and coexisting non-malignant pain (Van Beuken et al. 2007). The pain can either be
nociceptive (musculoskeletal, cutaneous or visceral) or neuropathic. About one third of patients with
cancer are believed to experience pain with a neuropathic component, many of whom experience a
mixed pain condition (Vadalouca et al. 2012).
The overall objective of treating cancer pain is to achieve pain relief and the highest possible quality
of life for the patient. Therapy should address all elements of the patient’s pain: cancer-related,
cancer-associated, therapy-related, and cancer-independent. As pain can be caused by multiple
different mechanisms, it is important that pain therapy reflects these underlying mechanisms
(Müller-Schwefe et al. 2014).
In identifying appropriate analgesics for patients with cancer, the prescribing clinician must consider
the agent’s efficacy, tolerability, onset of action, potential for interacting with other drugs the patient
is taking, its potential abuse liability, and cost. When prescribing opioids, the route of administration
must also be considered. Oral opioids are convenient for outpatients and frequently prescribed, but
are not suitable for patients who have difficulty swallowing or for whom there might be adherence
issues. Patients with severe pain requiring urgent relief should be treated with parenteral opioids
(subcutaneous or intravenous) or transmucosal products (Pergolizzi et al. 2015).
Thus there is definitely a need for medicines that have the potential for broad coverage of pain from
multiple origins and are available in multiple formulations to ensure optimal treatment options for
patients with cancer related pain.
4.2
Tramadol’s place in therapy
Tramadol is an established standard analgesic with a favorable risk-benefit profile, based on
worldwide data and experience of over 40 years and a cumulative patient exposure of more than 30
billion patient treatment days for tramadol containing-products worldwide (IMS Health Kilochem
data, 2015).
It has a particular place in situations where non-opioids such as paracetamol, NSAIDs and
cyclooxygenase (COX-2) inhibitors provide insufficient analgesia, are not tolerated, or are contraindicated, and where strong opioid analgesics are not yet warranted or are not sufficiently available.
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In cancer pain, tramadol alone or in combination with non-opioids can provide satisfactory analgesia
for moderate to severe levels of pain. Its efficacy is similar to that of lower doses of strong opioids
such as morphine. The relative potency of tramadol to morphine is about 1:5 for the oral route, and
1:10 for the parenteral route.
Tramadol is also a viable alternative to (high dose) NSAIDs and COX-2 inhibitors in longer-term
treatment and in the elderly, given the use-limiting safety issues associated with NSAIDs
(gastrointestinal bleeding) or NSAIDs as well as COX-2 inhibitors (cardiovascular risks,
nephrotoxicity) in this population. This will become even more important in the near future because
of the ageing of populations (UN World Aging population report 2015).
It is of note that due to its multiple modes of action (weak µ-opioid and non-opioid), tramadol
provides a unique analgesic profile that differentiates it from traditional opioids such as morphine or
codeine. Tramadol has not only shown efficacy in nociceptive pain but also in neuropathic pain and
is thus listed as a second line option (traditional opioids are third line) in the recent IASP guideline
on neuropathic pain (Finnerup et al. 2015). Arbaiza and Vidal (2007) also demonstrated that
tramadol can be considered a therapeutic option for cancer pain patients with a neuropathic pain
component.
Compared to traditional opioids, tramadol is associated with a lower incidence of typical µ-opioid
side effects (Grond and Sablotzky 2004). Most importantly, the risk of abuse and physical
dependence for tramadol is low in comparison to traditional opioids such as morphine. Also the risk
for serious opioid side effects such as respiratory depression is markedly lower than with traditional
opioids at doses with similar analgesic efficacy. This is of special relevance in the longer-term
treatment of cancer (or non-cancer pain), especially in the outpatient setting given that respiratory
depression is described as the most prominent mechanism causing fatal outcomes after acute opioid
intoxication (White 1999). Relative to the huge exposure worldwide, fatal toxicity involving
tramadol is rare (De Decker et al. 2008).
A further advantage of tramadol is that the best mode of administration can be selected for the
individual patient and the specific situation, because drops, capsules and PR preparations for oral
administration, suppositories and parenteral formulations for intramuscular, intravenous and
subcutanous injection are available.
Tramadol is available in the majority of the countries over the world providing a treatment option for
patients and doctors. This is different to other pain treatments like e.g. codeine. A recent publication
by Rico et al. 2016 summarized the situation for Latin America, showing that tramadol, different to
codeine, is broadly available with all its pharmaceutical forms.
4.3
Patient access
Even today 5.3 billion people (76% of the world population) live in countries with low to nonexistent access to controlled opioid analgesics (Duthey and Scholten 2014).
Tramadol has an important role to play here, as it is not controlled under the Single Convention on
Narcotic Drugs or under the United Nations Convention on Psychotropic Substances. It is available
as a regular prescription medicine in most countries worldwide. The range of tramadol containing
formulations is similar to those listed for the essential medicine morphine
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There are many situations where tramadol is the only option available for the treatment of moderate
severe cancer pain, given that it is accessible to in- and outpatients also in regions wherein controlled
strong opioids are not accessible.
Tramadol is recognized as a practical alternative in emergency situations where morphine is not
available (WHO, The Interagency Emergency Health Kit 2011).
- The problem of access to opioid analgesics is well recognized in the medical literature
In the past twenty years, WHO and the WHO Collaborating Centre for Pain Policy and Palliative
Care (Madison, WI, USA), together with the UN International Narcotics Control Board have
continuously shown that there is limited access to opioid analgesics in most countries around the
world. Two WHO studies showed that over 70% of the world population consumes per capita
less than 3% of the per capita consumption of the 20 most developed countries and 83% of the
world population (5.5 billion people) consumes less than 30%. (Seya et al. 2011, Duthey and
Scholten 2014). The difference between the country with the highest and the one with the lowest
consumption is 50,000 times, which is much more pronounced than the inequality for any other
group of medicines.
The European Society of Medical Oncology (ESMO) with participation of WHO led the Global
Opioid Policy Initiative and the European Opioid Policy Initiative. These two studies identified
which opioid medicines are available and regulations limiting their access by country and by
region (Cherny et al, 2010; Cleary et al, 2013 a-f). WHO and nine other organizations conducted
the ATOME project. This project identified regulations and other reasons for limited access in
twelve Eastern European Countries (Radbruch et al. 2014, Linge-Dahl et al. 2015; Larjow et al.
2016; Vranken et al. 2016). These studies led to the conclusion that still today controlled opioid
analgesics are barely available in developing countries (Seya et al. 2011; Human Right Watch
2011, Cleary et al. 2013 a-d, Duthey and Scholten 2014) and progress towards broader
availability is slow despite efforts from several organizations to improve access to these
medicines.
- WHO Policies related to promoting adequate pain management
The problem of limited access to opioid analgesics and the suffering related to this was
recognized by the international community in 2005 when the World Health Assembly adopted
resolution WHA58.22 (“Cancer prevention and control”) requesting the Director-General “to
examine jointly with the International Narcotics Control Board the feasibility of a possible
assistance mechanism that would facilitate the adequate treatment of pain using opioid
analgesics” (World Health Organization 2005). This resolution resulted in the WHO Access to
Controlled Medicines Program.
In 2014, the World Health Assembly adopted Resolution 67.19 (“Strengthening of palliative care
as a component of comprehensive care throughout the life course”). This resolution affirmed
“that access to palliative care and to essential medicines for medical and scientific purposes
manufactured from controlled substances, including opioid analgesics such as morphine, in line
with the three United Nations international drug control conventions, contributes to the
realization of the right to the enjoyment of the highest attainable standard of health and wellbeing” and noted “that the availability and appropriate use of internationally controlled medicines
for medical and scientific purposes, particularly for the relief of pain and suffering, remains
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insufficient in many countries”. Then, it requested the Director-General of WHO “to update or
develop, as appropriate, evidence-based guidelines and tools on palliation, including pain
management options, in adults and children, including the development of WHO guidelines for
the pharmacological treatment of pain, and ensure their adequate dissemination” (World Health
Organization 2014).
- Pain conditions expected to increase
It is also of note that the need for analgesic treatment is expected to increase in the next decades
due to an increasing elderly population. As the number of older people is projected to increase,
the incidence and prevalence of certain pain syndromes (e.g. pain from rheumatic diseases, pain
associated with atherosclerosis or diabetic neuropathy, cancer pain) is expected to increase as
well (Kay et al. 2010). Today, two thirds of the world’s older persons aged 60 and over live in
the developing regions (i.e. 602 million of 901 million worldwide) and their numbers are
growing faster there than in the developed regions (UN World Aging population report 2015).
Over the next 15 years, the number of elderly persons worldwide is expected to grow fastest in
Latin America and the Caribbean with a projected 71 per cent increase in the population aged 60
years or over, followed by Asia (66 per cent), Africa (64 per cent), Oceania (47 per cent),
Northern America (41 per cent) and Europe (23 per cent).
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CLINICAL EFFICACY
Tramadol has been developed for moderate to severe pain in a wide variety of clinical situations. For
the purpose of this application focus is on the efficacy of tramadol in cancer related pain. For
completeness, the efficacy of tramadol in non-cancer pain is briefly summarized at the end of the
section.
5.1
Efficacy in cancer related pain
In general, trials in patients in the terminal phase of cancer are extremely difficult to conduct
(Kongsgaard et al. 2009). The difficulties include the use of placebo, randomized withdrawal designs
that raise ethical concerns in this population, the interpretation of the data given the underlying
progressive disorder, and the patient’s preference to participate in clinical trials targeting the
underlying cancer disorder rather than in a clinical trial for the treatment of pain associated with
cancer. This has led to a general scarcity of good quality controlled clinical trials with analgesics in
cancer pain.
Guided by common practice, WHO has developed a three-step "ladder" for cancer pain relief in
adults, stipulating that if pain occurs, there should be prompt oral administration of drugs in the
following order: non-opioids; then, as necessary, addition of weak opioids; then strong opioids until
the patient is free of pain. Tramadol and codeine are considered as step-2 medicines by the WHO.
These medicines are to be considered either alone or in combination with step 1 analgesic treatments
when pain is persistent or increasing after treatment options with non-opioids have been exhausted
and before a switch is made to strong opioids such as morphine.
During the time that tramadol has been available in the clinic, several trials have been conducted in
cancer pain. A recent literature research (Embase Feb 10, 2017) using the terms tramadol, cancer
pain and randomized controlled trials yielded 191 results. In his systematic review published in 2011
Tassinari identified 18 publications of trials evaluating the efficacy of tramadol in cancer pain. All
had various shortcomings leading the authors to the conclusion that tramadol is an effective medicine
but the evidence supporting its front-line use is weak.
To our knowledge there are few trials establishing the efficacy of tramadol versus placebo in cancer
pain.
The trial published by Arbaiza and Vidal (2007) assessed the efficacy, safety and impact on quality
of life of tramadol in the treatment of neuropathic pain in patients with cancer. Patients were
randomised to receive either tramadol or placebo. The initial tramadol dosage was 1 mg/kg every 6
hours, increasing to 1.5 mg/kg every 6 hours if necessary to control pain. In the group receiving
tramadol (n = 18 of 36 enrolled), major improvements in pain intensity and Karnofsky scores
occurred (p < 0.001), sleep quality improved by day 45 (p < 0.05), activities of daily living improved
(p < 0.05) and use of analgesics that had been taken before the study was reduced (p < 0.05)
compared with the placebo group. The results of this study (with respect to better control of pain,
reduction in the use of antiepileptic analgesics, and improvement in Karnofsky scores and general
body function) show that tramadol can be considered as a therapeutic option for the control of
neuropathic pain in patients with cancer.
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Tramadol is a centrally acting analgesic with weak µ-opioid properties on WHO step 2, one question
to be addressed is if tramadol is a suitable alternative for other WHO step-2 medications such as
hydrocodone or codeine.
In this respect the study of Rodriguez at al. (2008) is relevant. They conducted a randomized
controlled trial in which patients with cancer receive either 25/2500 mg/day
hydrocodone/acetaminophen (n=62) or 200 mg/day tramadol (n=56). Pain relief was experienced by
73% of the patients who received tramadol and in 71% using hydrocodone/acetaminophen. This
difference was not statistically significant but nevertheless supports the place of tramadol as a step-2
analgesic on the WHO pain ladder.
Also the trial conducted by Oliva et al. (2000) is of relevance as it compared the effectiveness and
tolerance of tramadol versus dihydrocodeine, both administered through prolonged-release tablets
(PR) in patients with non-neurologic chronic pain associated to prostate cancer. It was a crossover,
triple blind clinical trial at phase IV. Thirty-two patients with prostate cancer and bone metastasis,
previously treated with non-steroid anti-inflammatory drugs (WHO Step 1) alone or together with
codeine (WHO Step 2), were randomized to two groups of 16 patients each. Group 1 received
tramadol PR 100 mg each 12 hours for the first 14 days and dihydrocodeine PR 90 mg each 12 hours
for the next 14 days. In Group 2: vice versa. If pain could not be controlled with such doses, the dose
was doubled. Both analgesics decreased pain severity, according to the numerical scale, to less than 3
compared to initial averages of 7.09, with results favorable to tramadol PR.
Studies comparing tramadol with morphine revealed equal or at worst somewhat lower efficacy
morphine and a better tolerability profile for tramadol (Wilder-Smith 1994, Leppert 2001, Tawfik
1990). The study of Wilder-Smith showed no difference of pain intensity after 4 days of treatment
between morphine and tramadol with less intense adverse events in the tramadol group.
Comparison of high dose tramadol with low dose morphine in a retrospective study with 810 patients
on oral tramadol (up to 600mg/d) and 848 patients on oral morphine (up to 60mg/d) led to the
conclusion that at these doses tramadol and morphine are equally effective in the treatment of cancer
pain. Constipation, neuropsychological symptoms, and pruritus were observed significantly more
frequently with low-dose morphine; other symptoms had similar frequencies in both groups (Grond
1999). Although morphine’s efficacy in cancer pain was superior to tramadol’s, this was offset by
more use limiting side effects, including signs of respiratory depression, of morphine (Osipova NA et
al 1991).
Furthermore Bono et al (1997) demonstrated in a cross-over study in 60 patients, that oral tramadol
(300mg/d for 7 days) had an analgesic effect similar to sublingual buprenorphine (0.6mg/d for 7
days) but was better tolerated. A study with long term treatment for up to six months (mean
treatment days 58 for tramadol and 51 for buprenorphine) showed a similar pain relief profile of
tramadol and buprenorphine. Dosages of 200-300mg/day of tramadol were high enough to provide
adequate pain relief without occurrence of troublesome side effects, tolerance or drug-dependence
development (Brema et al 1996).
Leppert (2009) compared in his review article available clinical data on tramadol with other opioids
for the treatment of mild to moderate cancer pain and found tramadol of importance because of its
efficacy, favorable safety profile, and its availability in different formulations as well as the potential
for combination with non-opioid analgesics such as paracetamol.
Last but not least, tramadol was proven to be safe and efficacious in children in two open label trials
(Kralinsky et al 1994, Rose et al 2003). In these trials children with various pain conditions including
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cancer pain were treated. Administration of tramadol resulted in pain relief with a side effect profile
similar to that observed in adults (Rose 2003).
In conclusion, the available literature supports the use of tramadol as an effective agent for the
treatment of moderate to severe cancer pain. It has demonstrated effects on nociceptive and
neuropathic cancer pain. The analgesic effect has been studied and confirmed in adults and children
suffering from moderate to severe cancer pain. Moreover given that there are only very limited
options for step 2 analgesia prior to moving to strong opioid analgesics, it is justified to include
tramadol on the WHO Model List of Essential Medicines.
5.2
Efficacy in non-cancer pain
Grünenthal and partners have confirmed tramadol’s safety and efficacy in about 150 randomized,
controlled clinical trials in many acute pain conditions (e.g. postoperative pain, pain after wisdom
tooth removal, burn pain) and chronic pain conditions (e.g. osteoarthritis, chronic low back pain,
neuropathic pain and pain associated with fibromyalgia). As a whole, these trials confirmed that
tramadol’s efficacy is superior to placebo and is at least equivalent, if not superior, to active
comparators such as paracetamol, non-steroidals, codeine, dextropropoxyphene, nalbuphine and low
dose morphine.
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6.1
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SAFETY AND TOXICITY
Adverse event profile and comparative safety vs traditional opioids
Tramadol is established as an analgesic with a favorable risk-benefit profile based on worldwide data
and experience of over 40 years. Tramadol has been extensively studied also in the pediatric
population and its safe use in children was confirmed by the European Medicines Agency (EMA) in
2015.
Common adverse reactions occurring following tramadol administration are qualitatively similar to
other centrally acting analgesics and include dizziness and nausea (observed in more than 10% of the
patients), vomiting, headache, dry mouth, constipation and sweating (observed in 1-10% of patients)
(GRT CCDS, vs 18).
Compared to traditional opioids (e.g. morphine, oxycodone, pethidine, nalbuphine) clinical studies
with tramadol in patients demonstrate a more favourable safety profile with regards to the
cardiovascular system (Ellmauer et al. 1994), respiratory function (Bosenberg and Ratcliffe 1998,
Houmes et al. 1992, Langford et al. 1998, Mildh 1999, Tarkkila et al. 1997, Tarkkilla et al. 1998,
Schaffer et al. 1986, Vickers and Paravicini 1995), immuno-supression (Sacerdote et al. 1997,
Sacerdote et al. 1999, Sacerdote et al. 2000), gastrointestinal motor function (Wilder-Smith and
Bettiga 1997, Wilder Smith et al. 1999) and contraction of gastrointestinal sphincters (Staritz et al.
1986).
Respiratory depression is a typical serious side effect of µ-opioid receptor agonists. The risk is
increased if recommended doses are considerably exceeded and other centrally depressant substances
are administered concomitantly. Due to its multiple modes of action, tramadol has a lower propensity
to cause respiratory depression compared to pure µ-opioid receptor agonists. Several clinical trials
with tramadol clearly demonstrate that in comparison to traditional opioids such as morphine,
oxycodone, pethidine or nalbuphine, tramadol combines a good analgesic effect with a lower risk of
respiratory depression (Houmes et al. 1992, Vickers and Paravicini 1995, Langford et al. 1998,
Tarkkila et al. 1997, Tarkkila et al. 1998, Bosenberg et al. 1988, Mildh et al. 1999, Schaffer et al.
1986). Only following excessive dosage such as in overdose situations, tramadol may produce
relevant respiratory depression (Shipton et al. 2000, Scott et al. 2000). In addition, several reviews
show that the mortality rate after tramadol overdose alone is low (Ripple et al. 2000, Musshoff et al.
2001, Daubin et al. 2007, Shadnia et al. 2008).
Like many other opioids, tramadol can induce seizure. In patients without predisposing conditions
and in the absence of proconvulsant co-medication, the seizure risk after intake of therapeutic
dosages of tramadol is low and case control studies in very large populations indicate that the seizure
risk is not increased as compared to other pain medications (Jick et al. 1998, Gasse et al. 2000,
Gardner et al. 2000, Raffa and Stone 2008). Convulsion occurred mainly after administration of high
doses of tramadol or after concomitant treatment with medicinal products which can lower the
seizure threshold.
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors, tricyclic
antidepressants and mirtazapine, may cause serotonin toxicity (GRT CCDS, vs. 18). It is unlikely
that a single serotonergic substance would cause serotonin syndrome and there is no substantial
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evidence that the use of tramadol alone is associated with serotonin toxicity, based on continuous
pharmacovigilance activities performed in the context of periodic reporting submission (Dunkley et
al. 2003, Isbister et al. 2007).
6.2
Abuse potential vs traditional opioids
Tramadol has a low abuse potential compared to traditional opioid analgesics such as morphine.
Low abuse levels of tramadol containing products worldwide were consistently shown in data from
epidemiological and post-marketing surveillance studies, including Grünenthal’s Global Drug Safety
database, several monitoring systems in the United States of America (USA) and Germany, and the
World Health Organization (WHO) Collaborating Centre for International Drug Monitoring.
After a peak for abuse/dependence case reports occurring after the first marketing authorization in
the USA in 1995, the relative reporting rate (case reports/estimated exposure) continuously
decreased. Since 2008 the relative reporting rate is stable and remains below 0.3 per million patienttreatment-days.
The Researched Abuse, Diversion and Addiction-related Surveillance (RADARS) System is
designed to provide timely surveillance and monitoring data to characterize prescription drug abuse,
misuse and diversion in the USA. Tramadol has been incorporated into this monitoring program in
2005. Recent data continue to indicate that tramadol abuse is low on all measures (Schneider et al.
2009, WHO ECDD 2014 – GRT supplemental tramadol data).
In a comparative study (n=11352) the prevalence of tramadol abuse has been compared to
nonsteroidal anti-inflammatory drugs (NSAIDs) and hydrocodone in patients with chronic pain. The
rate of abuse identified with tramadol was not significantly greater than NSAIDs, but was less than
with hydrocodone. Furthermore, abuse/dependence in this population was low overall and consistent
with other studies of large patient populations (Adams et al. 2006). In a post-authorization safety
study including 1601 impaired health care professionals in the USA who are a high risk/high access
population for drug abuse (Knisely 2002), it was concluded that, despite availability of tramadol the
incidence rate for tramadol abuse/addiction was only 6.9 per thousand persons per year. This finding
supports the contention that the risk of abuse of tramadol is indeed low. In addition, this study
observed that those who abused tramadol were previous abusers of opioids.
It is acknowledged, that a limited number of countries, particularly Egypt as well as the African and
Middle East regions, face illicit trafficking and abuse of tramadol. However, national control
activities appear to be successful as e.g. trafficking in Egypt decreased by around 64% between 2012
and 2014 (INCB 2016). Furthermore, the problem of abuse and illicit trafficking is not restricted to
tramadol alone and can be seen in the context of the political and social instabilities in this region.
If abuse/addiction occurs, it is in the vast majority of case reports obtained from the Global
Grünenthal Drug Safety Database, typically limited to persons with a history of substance abuse. In a
recent publication, Roussin et al. (2014) performed an evaluation of the abuse and dependence
potential of tramadol based on data obtained from pharmacoepidemiological tools used by the
French network for pharmacodependence and addiction monitoring. The authors state that
comparison of data from spontaneous reports with surveys in specific populations and with
evaluations of indicators of diverted uses did not highlight a major problem of tramadol abuse and
dependence in terms of public health.
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In 2014 the World Health Organization's Expert Committee on Drug dependence (ECDD) assessed
worldwide data on tramadol abuse and came to the decision that no critical review is warranted, i.e.
international control for tramadol is not warranted (WHO ECDD 2014).
6.3
Safety profile of potential alternatives in mild to moderate pain
NSAIDs are recommended by the WHO as Step 1 in the management of cancer pain. Their efficacy
is inferior to tramadol and their maximum daily dose is limited by safety concerns. Treatment with
NSAIDs is associated with a 3-fold to 5-fold increase in the risk of upper gastrointestinal
complications, including peptic ulcer, perforation, obstruction, and bleeding. The kidney is another
important target site for NSAIDs untoward effects, with renal events occurring in 1% to 5% of all
patients using NSAIDs (Whelton 1999). Substituting COX-2-inhibitors for regular NSAIDs may
reduce the incidence of GI events, but not the nephrotoxicity profile. In addition, studies have
implied an increased cardiovascular event rate associated with COX-2-inhibitors. More recently, it
became apparent that this may not be a problem with COX-2-inhibitors only, but also with nonselective NSAIDs. As a result, the European Medicines Agency has issued an opinion that NSAIDs
should be prescribed at the lowest effective dose and for the shortest duration necessary to control
symptoms (EMA 2006).
Paracetamol might also be prescribed as an alternative for tramadol, but cannot reach the same
analgesic efficacy. In addition, for safety reasons, regulatory authorities worldwide have limited the
maximum daily dose of paracetamol, preventing patients to increase the dose in case of insufficient
pain control. The major concern of the authorities is related to hepatotoxicity, which remains the
leading cause of acute liver failure in the UK, North America and Europe and represents a significant
health care burden (Craig et al. 2011).
Codeine hardly has any pharmacological activity by itself and is dependent upon hepatic CYP2D6
mediated O-demethylation to morphine to display its effects. Consequently, the analgesic effect of
codeine is based only on the opioid agonistic activity, while tramadol has a dual mode of action
comprising an opioid and mono-aminergic component. As a consequence, the same analgesic effect
can be reached in case of tramadol with a lower dose of “opioid component”, than in case of codeine.
In poor metabolizers (PMs) codeine is completely inactive (Sindrup et al. 1990) due to the absence
of formation of morphine. In these subjects, tramadol retains the (clinically relevant) monoaminergic part of its analgesic activity (Desmeules et al. 1996, Eggers and Power 1995, Stamer et al.
2003). In ultra-rapid metabolizers (UMs) the conversion of codeine to morphine and of tramadol to
M1 is increased to a similar extent (Kirchheiner et al. 2007; Kirchheiner et al. 2008). The safety of
codeine and tramadol in UMs, and particularly in infants and children, is considered to be completely
different due to the different pharmacokinetic fates and pharmacodynamic profiles of their
metabolites morphine and M1. In contrast to tramadol, pain treatment with codeine is contraindicated
in children (PRAC 2015).
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Mildh LH, Leino KA, Kirvelä OA. Effects of tramadol and meperidine on respiration, plasma
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Müller-Schwefe et al. 2014
Musshoff F, Madea B. Fatality due to ingestion of tramadol alone. Forensic Sci Int 2001; 116: 197199.
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Grünenthal
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
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http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Paediatric_Regulation/Assessme
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Model List of Essential Medicines (EML) 2017
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Model List of Essential Medicines (EML) 2017
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8
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
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ANNEXES
ANNEX 1: International availability of tramadol
Table 1:
Overview of tramadol’s international availability based on IMS Health Kilochem
Study data 2016. Low and middle income countries are highlighted in grey.
(non-exhaustive list as IMS does not provide information for all countries).
Listed countries:
- 76 countries
Formulations:
- Oral liquids IR:
- Oral solid IR:
- Oral solid PR:
- Parenteral IR:
- Rectal IR:
COUNTRY
ALGERIA
ALGERIA
ALGERIA
ALGERIA
ARGENTINA
ARGENTINA
ARGENTINA
ARGENTINA
AUSTRALIA
AUSTRALIA
AUSTRALIA
AUSTRALIA
AUSTRIA
AUSTRIA
AUSTRIA
AUSTRIA
AUSTRIA
BANGLADESH
BANGLADESH
BANGLADESH
BANGLADESH
BELGIUM
BELGIUM
BELGIUM
BELGIUM
50 countries
75 countries
72 countries
73 countries
41 countries
AVAILABLE FORMULATIONS
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
PARENTERAL IR
RECTAL IR
Grünenthal
BOSNIA
BOSNIA
BOSNIA
BOSNIA
BOSNIA
BRAZIL
BRAZIL
BRAZIL
BRAZIL
BULGARIA
BULGARIA
C. AMERICA
C. AMERICA
C. AMERICA
C. AMERICA
CANADA
CANADA
CHILE
CHILE
CHILE
CHILE
CHILE
CHINA
CHINA
CHINA
CHINA
CHINA
COLOMBIA
COLOMBIA
COLOMBIA
COLOMBIA
CROATIA
CROATIA
CROATIA
CROATIA
CROATIA
CZECH
CZECH
CZECH
CZECH
CZECH
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
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Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
DENMARK
DENMARK
DENMARK
DENMARK
DENMARK
DOMINICAN REPUBLIC
DOMINICAN REPUBLIC
DOMINICAN REPUBLIC
DOMINICAN REPUBLIC
ECUADOR
ECUADOR
ECUADOR
ECUADOR
EGYPT
EGYPT
EGYPT
EGYPT
EGYPT
ESTONIA
ESTONIA
ESTONIA
ESTONIA
ESTONIA
FINLAND
FINLAND
FINLAND
FINLAND
FINLAND
FR. W. AFRICA
FR. W. AFRICA
FR. W. AFRICA
FR. W. AFRICA
FR. W. AFRICA
FRANCE
FRANCE
FRANCE
FRANCE
GERMANY
GERMANY
GERMANY
GERMANY
GERMANY
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
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Grünenthal
GREECE
GREECE
GREECE
GREECE
GREECE
HONG KONG
HONG KONG
HONG KONG
HONG KONG
HONG KONG
HUNGARY
HUNGARY
HUNGARY
HUNGARY
HUNGARY
INDIA
INDIA
INDIA
INDIA
INDONESIA
INDONESIA
INDONESIA
INDONESIA
IRELAND
IRELAND
IRELAND
ITALY
ITALY
ITALY
ITALY
ITALY
JAPAN
JAPAN
JAPAN
JORDAN
JORDAN
JORDAN
JORDAN
KAZAKHSTAN
KAZAKHSTAN
KAZAKHSTAN
KAZAKHSTAN
KUWAIT
KUWAIT
KUWAIT
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
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Grünenthal
LATVIA
LATVIA
LATVIA
LATVIA
LATVIA
LEBANON
LEBANON
LEBANON
LEBANON
LEBANON
LITHUANIA
LITHUANIA
LITHUANIA
LITHUANIA
LITHUANIA
LUXEMBOURG
LUXEMBOURG
LUXEMBOURG
LUXEMBOURG
LUXEMBOURG
MALAYSIA
MALAYSIA
MALAYSIA
MALAYSIA
MEXICO
MEXICO
MEXICO
MEXICO
MOROCCO
MOROCCO
MOROCCO
MOROCCO
NETHERLANS
NETHERLANS
NETHERLANS
NETHERLANS
NETHERLANS
NEW ZEALAND
NEW ZEALAND
NEW ZEALAND
NEW ZEALAND
NORWAY
NORWAY
NORWAY
NORWAY
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
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PAKISTAN
PAKISTAN
PAKISTAN
PERU
PERU
PERU
PERU
PHILIPPINES
PHILIPPINES
PHILIPPINES
POLAND
POLAND
POLAND
POLAND
PORTUGAL
PORTUGAL
PORTUGAL
PORTUGAL
PORTUGAL
PUERTO RICO
PUERTO RICO
ROMANIA
ROMANIA
ROMANIA
ROMANIA
ROMANIA
RUSSIA
RUSSIA
RUSSIA
RUSSIA
S. AFRICA
S. AFRICA
S. AFRICA
S. AFRICA
S. KOREA
S. KOREA
S. KOREA
SAUDI ARABIA
SAUDI ARABIA
SAUDI ARABIA
SAUDI ARABIA
SERBIA
SERBIA
SERBIA
SERBIA
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
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SINGAPORE
SINGAPORE
SINGAPORE
SLOVAKIA
SLOVAKIA
SLOVAKIA
SLOVAKIA
SLOVAKIA
SLOVENIA
SLOVENIA
SLOVENIA
SLOVENIA
SLOVENIA
SPAIN
SPAIN
SPAIN
SPAIN
SPAIN
SRI LANKA
SRI LANKA
SWEDEN
SWEDEN
SWEDEN
SWEDEN
SWITZERLAND
SWITZERLAND
SWITZERLAND
SWITZERLAND
SWITZERLAND
TAIWAN
TAIWAN
TAIWAN
THAILAND
THAILAND
THAILAND
TUNISIA
TUNISIA
TUNISIA
TUNISIA
TUNISIA
TURKEY
TURKEY
TURKEY
TURKEY
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
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Grünenthal
Comments to the
Application for inclusion of tramadol into the WHO
Model List of Essential Medicines (EML) 2017
UKRAINE
UKRAINE
UNITED ARAB EMIRATES
UNITED ARAB EMIRATES
UNITED ARAB EMIRATES
UNITED ARAB EMIRATES
UNITED KINGDOM
UNITED KINGDOM
UNITED KINGDOM
UNITED KINGDOM
UNITED STATES
UNITED STATES
URUGUAY
URUGUAY
URUGUAY
URUGUAY
URUGUAY
VENEZUELA
VENEZUELA
VENEZUELA
VENEZUELA
VIETNAM
VIETNAM
VIETNAM
ORAL SOLID IR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
RECTAL IR
ORAL LIQUIDS IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
ORAL SOLID IR
ORAL SOLID PR
PARENTERAL IR
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