Page 1 of 33 - WHO...Page 1 of 33 TRAMADOL Comments on the EML application for inclusion of opioid analgesics for cancer pain: fentanyl, methadone, tramadol 21st WHO Expert Committee

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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 PHARMACOTHERAPY 5 3.1 Pharmacology of tramadol 5 3.2 Treatment details 5 3.3 Guideline recommendations 7

4 PUBLIC HEALTH RELEVANCE 9 4.1 Disease burden 9 4.2 Tramadol’s place in therapy 9 4.3 Patient access 10

5 CLINICAL EFFICACY 13 5.1 Efficacy in cancer related pain 13 5.2 Efficacy in non-cancer pain 15

6 SAFETY AND TOXICITY 16 6.1 Adverse event profile and comparative safety vs traditional opioids 16 6.2 Abuse potential vs traditional opioids 17 6.3 Safety profile of potential alternatives in mild to moderate pain 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

IMS

Grünenthal Core Company Data Sheet

Intercontinental Marketing Services

IR Immediate release

PR Prolonged release

PM Poor metabolizer

WHO World Health Organization



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1 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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2 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, prolonged-release 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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3 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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- 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 (N-desmethylation, 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 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-y-Cuidados-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/LIBRO%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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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 PUBLIC HEALTH RELEVANCE

4.1 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 contra-indicated, 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 non-existent 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 well-being” 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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5 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 SAFETY AND TOXICITY

6.1 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 patient-treatment-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 non-selective 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) mono-aminergic 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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8 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: 50 countries - Oral solid IR: 75 countries - Oral solid PR: 72 countries - Parenteral IR: 73 countries - Rectal IR: 41 countries

COUNTRY AVAILABLE FORMULATIONS ALGERIA ORAL SOLID IR ALGERIA ORAL SOLID PR ALGERIA PARENTERAL IR ALGERIA RECTAL IR ARGENTINA ORAL LIQUIDS IR ARGENTINA ORAL SOLID IR ARGENTINA ORAL SOLID PR ARGENTINA PARENTERAL IR AUSTRALIA ORAL LIQUIDS IR AUSTRALIA ORAL SOLID IR AUSTRALIA ORAL SOLID PR AUSTRALIA PARENTERAL IR AUSTRIA ORAL LIQUIDS IR AUSTRIA ORAL SOLID IR AUSTRIA ORAL SOLID PR AUSTRIA PARENTERAL IR AUSTRIA RECTAL IR BANGLADESH ORAL SOLID IR BANGLADESH ORAL SOLID PR BANGLADESH PARENTERAL IR BANGLADESH RECTAL IR BELGIUM ORAL LIQUIDS IR BELGIUM ORAL SOLID IR BELGIUM PARENTERAL IR BELGIUM RECTAL IR



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BOSNIA ORAL LIQUIDS IR BOSNIA ORAL SOLID IR BOSNIA ORAL SOLID PR BOSNIA PARENTERAL IR BOSNIA RECTAL IR BRAZIL ORAL LIQUIDS IR BRAZIL ORAL SOLID IR BRAZIL ORAL SOLID PR BRAZIL PARENTERAL IR BULGARIA ORAL SOLID IR BULGARIA PARENTERAL IR C. AMERICA ORAL LIQUIDS IR C. AMERICA ORAL SOLID IR C. AMERICA ORAL SOLID PR C. AMERICA PARENTERAL IR CANADA ORAL SOLID IR CANADA ORAL SOLID PR CHILE ORAL LIQUIDS IR CHILE ORAL SOLID IR CHILE ORAL SOLID PR CHILE PARENTERAL IR CHILE RECTAL IR CHINA ORAL LIQUIDS IR CHINA ORAL SOLID IR CHINA ORAL SOLID PR CHINA PARENTERAL IR CHINA RECTAL IR COLOMBIA ORAL LIQUIDS IR COLOMBIA ORAL SOLID IR COLOMBIA ORAL SOLID PR COLOMBIA PARENTERAL IR CROATIA ORAL LIQUIDS IR CROATIA ORAL SOLID IR CROATIA ORAL SOLID PR CROATIA PARENTERAL IR CROATIA RECTAL IR CZECH ORAL LIQUIDS IR CZECH ORAL SOLID IR CZECH ORAL SOLID PR CZECH PARENTERAL IR CZECH RECTAL IR



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DENMARK ORAL LIQUIDS IR DENMARK ORAL SOLID IR DENMARK ORAL SOLID PR DENMARK PARENTERAL IR DENMARK RECTAL IR DOMINICAN REPUBLIC ORAL LIQUIDS IR DOMINICAN REPUBLIC ORAL SOLID IR DOMINICAN REPUBLIC ORAL SOLID PR DOMINICAN REPUBLIC PARENTERAL IR ECUADOR ORAL LIQUIDS IR ECUADOR ORAL SOLID IR ECUADOR ORAL SOLID PR ECUADOR PARENTERAL IR EGYPT ORAL LIQUIDS IR EGYPT ORAL SOLID IR EGYPT ORAL SOLID PR EGYPT PARENTERAL IR EGYPT RECTAL IR ESTONIA ORAL LIQUIDS IR ESTONIA ORAL SOLID IR ESTONIA ORAL SOLID PR ESTONIA PARENTERAL IR ESTONIA RECTAL IR FINLAND ORAL LIQUIDS IR FINLAND ORAL SOLID IR FINLAND ORAL SOLID PR FINLAND PARENTERAL IR FINLAND RECTAL IR FR. W. AFRICA ORAL LIQUIDS IR FR. W. AFRICA ORAL SOLID IR FR. W. AFRICA ORAL SOLID PR FR. W. AFRICA PARENTERAL IR FR. W. AFRICA RECTAL IR FRANCE ORAL LIQUIDS IR FRANCE ORAL SOLID IR FRANCE ORAL SOLID PR FRANCE PARENTERAL IR GERMANY ORAL LIQUIDS IR GERMANY ORAL SOLID IR GERMANY ORAL SOLID PR GERMANY PARENTERAL IR GERMANY RECTAL IR



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GREECE ORAL LIQUIDS IR GREECE ORAL SOLID IR GREECE ORAL SOLID PR GREECE PARENTERAL IR GREECE RECTAL IR HONG KONG ORAL LIQUIDS IR HONG KONG ORAL SOLID IR HONG KONG ORAL SOLID PR HONG KONG PARENTERAL IR HONG KONG RECTAL IR HUNGARY ORAL LIQUIDS IR HUNGARY ORAL SOLID IR HUNGARY ORAL SOLID PR HUNGARY PARENTERAL IR HUNGARY RECTAL IR INDIA ORAL SOLID IR INDIA ORAL SOLID PR INDIA PARENTERAL IR INDIA RECTAL IR INDONESIA ORAL SOLID IR INDONESIA ORAL SOLID PR INDONESIA PARENTERAL IR INDONESIA RECTAL IR IRELAND ORAL SOLID IR IRELAND ORAL SOLID PR IRELAND PARENTERAL IR ITALY ORAL LIQUIDS IR ITALY ORAL SOLID IR ITALY ORAL SOLID PR ITALY PARENTERAL IR ITALY RECTAL IR JAPAN ORAL SOLID IR JAPAN ORAL SOLID PR JAPAN PARENTERAL IR JORDAN ORAL LIQUIDS IR JORDAN ORAL SOLID IR JORDAN ORAL SOLID PR JORDAN PARENTERAL IR KAZAKHSTAN ORAL SOLID IR KAZAKHSTAN ORAL SOLID PR KAZAKHSTAN PARENTERAL IR KAZAKHSTAN RECTAL IR KUWAIT ORAL SOLID IR KUWAIT ORAL SOLID PR KUWAIT PARENTERAL IR



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LATVIA ORAL LIQUIDS IR LATVIA ORAL SOLID IR LATVIA ORAL SOLID PR LATVIA PARENTERAL IR LATVIA RECTAL IR LEBANON ORAL LIQUIDS IR LEBANON ORAL SOLID IR LEBANON ORAL SOLID PR LEBANON PARENTERAL IR LEBANON RECTAL IR LITHUANIA ORAL LIQUIDS IR LITHUANIA ORAL SOLID IR LITHUANIA ORAL SOLID PR LITHUANIA PARENTERAL IR LITHUANIA RECTAL IR LUXEMBOURG ORAL LIQUIDS IR LUXEMBOURG ORAL SOLID IR LUXEMBOURG ORAL SOLID PR LUXEMBOURG PARENTERAL IR LUXEMBOURG RECTAL IR MALAYSIA ORAL SOLID IR MALAYSIA ORAL SOLID PR MALAYSIA PARENTERAL IR MALAYSIA RECTAL IR MEXICO ORAL LIQUIDS IR MEXICO ORAL SOLID IR MEXICO ORAL SOLID PR MEXICO PARENTERAL IR MOROCCO ORAL SOLID IR MOROCCO ORAL SOLID PR MOROCCO PARENTERAL IR MOROCCO RECTAL IR NETHERLANS ORAL LIQUIDS IR NETHERLANS ORAL SOLID IR NETHERLANS ORAL SOLID PR NETHERLANS PARENTERAL IR NETHERLANS RECTAL IR NEW ZEALAND ORAL LIQUIDS IR NEW ZEALAND ORAL SOLID IR NEW ZEALAND ORAL SOLID PR NEW ZEALAND PARENTERAL IR NORWAY ORAL LIQUIDS IR NORWAY ORAL SOLID IR NORWAY ORAL SOLID PR NORWAY PARENTERAL IR



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PAKISTAN ORAL SOLID IR PAKISTAN ORAL SOLID PR PAKISTAN PARENTERAL IR PERU ORAL LIQUIDS IR PERU ORAL SOLID IR PERU ORAL SOLID PR PERU PARENTERAL IR PHILIPPINES ORAL SOLID IR PHILIPPINES ORAL SOLID PR PHILIPPINES PARENTERAL IR POLAND ORAL LIQUIDS IR POLAND ORAL SOLID PR POLAND PARENTERAL IR POLAND RECTAL IR PORTUGAL ORAL LIQUIDS IR PORTUGAL ORAL SOLID IR PORTUGAL ORAL SOLID PR PORTUGAL PARENTERAL IR PORTUGAL RECTAL IR PUERTO RICO ORAL SOLID IR PUERTO RICO ORAL SOLID PR ROMANIA ORAL LIQUIDS IR ROMANIA ORAL SOLID IR ROMANIA ORAL SOLID PR ROMANIA PARENTERAL IR ROMANIA RECTAL IR RUSSIA ORAL SOLID IR RUSSIA ORAL SOLID PR RUSSIA PARENTERAL IR RUSSIA RECTAL IR S. AFRICA ORAL SOLID IR S. AFRICA ORAL SOLID PR S. AFRICA PARENTERAL IR S. AFRICA RECTAL IR S. KOREA ORAL SOLID IR S. KOREA ORAL SOLID PR S. KOREA PARENTERAL IR SAUDI ARABIA ORAL SOLID IR SAUDI ARABIA ORAL SOLID PR SAUDI ARABIA PARENTERAL IR SAUDI ARABIA RECTAL IR SERBIA ORAL LIQUIDS IR SERBIA ORAL SOLID IR SERBIA ORAL SOLID PR SERBIA PARENTERAL IR



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SINGAPORE ORAL SOLID IR SINGAPORE ORAL SOLID PR SINGAPORE PARENTERAL IR SLOVAKIA ORAL LIQUIDS IR SLOVAKIA ORAL SOLID IR SLOVAKIA ORAL SOLID PR SLOVAKIA PARENTERAL IR SLOVAKIA RECTAL IR SLOVENIA ORAL LIQUIDS IR SLOVENIA ORAL SOLID IR SLOVENIA ORAL SOLID PR SLOVENIA PARENTERAL IR SLOVENIA RECTAL IR SPAIN ORAL LIQUIDS IR SPAIN ORAL SOLID IR SPAIN ORAL SOLID PR SPAIN PARENTERAL IR SPAIN RECTAL IR SRI LANKA ORAL SOLID IR SRI LANKA PARENTERAL IR SWEDEN ORAL LIQUIDS IR SWEDEN ORAL SOLID IR SWEDEN ORAL SOLID PR SWEDEN PARENTERAL IR SWITZERLAND ORAL LIQUIDS IR SWITZERLAND ORAL SOLID IR SWITZERLAND ORAL SOLID PR SWITZERLAND PARENTERAL IR SWITZERLAND RECTAL IR TAIWAN ORAL SOLID IR TAIWAN ORAL SOLID PR TAIWAN PARENTERAL IR THAILAND ORAL SOLID IR THAILAND ORAL SOLID PR THAILAND PARENTERAL IR TUNISIA ORAL LIQUIDS IR TUNISIA ORAL SOLID IR TUNISIA ORAL SOLID PR TUNISIA PARENTERAL IR TUNISIA RECTAL IR TURKEY ORAL LIQUIDS IR TURKEY ORAL SOLID IR TURKEY ORAL SOLID PR TURKEY PARENTERAL IR



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UKRAINE ORAL SOLID IR UKRAINE PARENTERAL IR UNITED ARAB EMIRATES ORAL LIQUIDS IR UNITED ARAB EMIRATES ORAL SOLID IR UNITED ARAB EMIRATES ORAL SOLID PR UNITED ARAB EMIRATES PARENTERAL IR UNITED KINGDOM ORAL LIQUIDS IR UNITED KINGDOM ORAL SOLID IR UNITED KINGDOM ORAL SOLID PR UNITED KINGDOM PARENTERAL IR UNITED STATES ORAL SOLID IR UNITED STATES ORAL SOLID PR URUGUAY ORAL LIQUIDS IR URUGUAY ORAL SOLID IR URUGUAY ORAL SOLID PR URUGUAY PARENTERAL IR URUGUAY RECTAL IR VENEZUELA ORAL LIQUIDS IR VENEZUELA ORAL SOLID IR VENEZUELA ORAL SOLID PR VENEZUELA PARENTERAL IR VIETNAM ORAL SOLID IR VIETNAM ORAL SOLID PR VIETNAM PARENTERAL IR

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Page 1 of 33 - WHO...Page 1 of 33 TRAMADOL Comments on the EML application for inclusion of opioid analgesics for cancer pain: fentanyl, methadone, tramadol 21st WHO Expert Committee