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SDR-BASIC-TEMPLATE-02

TRAMADOL

Comments to the World Health Organization (WHO; Expert Committee on Drug Dependence)

Tramadol Update Review Report 2014

Prepared by:

Grünenthal GmbH, Germany

Submitted by:

International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Switzerland

for the World Health Organization

23 May 2014

Grünenthal Comments to the

WHO (ECDD) Tramadol Update Review Report 2014

Page 2 of 11 23 May 2014 DMS-ver 1.0

TABLE OF CONTENTS

TABLE OF CONTENTS 2

LIST OF ABBREVIATIONS 2

1 EXECUTIVE SUMMARY 3

2 DETAILED COMMENTS AND SUPPORTIVE INFORMATION 4 2.1 Evidence of analgesic effect of tramadol 4 2.2 Evidence on illicit manufacture and traffic 6 2.3 Impact of scheduling on the medical availability of tramadol 7 2.3.1 Role in clinical practice 7 2.3.2 Impact of an international control on tramadol’s medical availability 8

3 REFERENCES 8 3.1 Supportive statements 8 3.2 Guidelines 9 3.3 Literature 9

LIST OF ABBREVIATIONS

Abbreviation Explanation Cox-II Cyclooxygenase-II ECDD Expert Committee on Drug Dependence FDA United States Food and Drug Administration INCB International Narcotics Control Board NSAID non-steroidal anti-inflammatory drug UNODC United Nations Office of Drugs and Crime US United States of America WHO World Health Organization




1 EXECUTIVE SUMMARY

Grünenthal is convinced that the available data overall continue to support the conclusion that tramadol should not be placed under international control. This enables national decisions on required measures to achieve an appropriate balance between effective minimization of abuse and ensuring availability for medical purposes.

Need of the substance for medical practice Tramadol is authorized for moderate to (moderately) severe pain in more than 100 countries worldwide.

The efficacy of tramadol has been established based on more than 350 randomized, controlled, clinical trials, conducted by pharmaceutical industry or by independent investigators in a wide range of indications with moderate to severe acute and chronic pain. Particularly, the efficacy of tramadol monotherapy has been shown in various acute and chronic pain models including post-operative pain, dental pain, pain due to trauma, abdominal pain, labor pain, as well as cancer pain, pain due to osteoarthritis, chronic low back pain, neuropathic pain, and fibromyalgia.

Also, tramadol is recommended by the WHO as a step 2 analgesic (WHO 1996).

Meta-analyses by Cochrane and others as well as evidence based treatment recommendations by pain societies worldwide provide support that tramadol is an efficacious, versatile and useful analgesic, particularly in situations where paracetamol, NSAIDs and cyclooxygenase (Cox)-II inhibitors provide insufficient analgesia, are not tolerated, or are contra-indicated, and where there is hesitation to use strong opioids.

In spite of the available convincing evidence, the WHO Tramadol Update Review Report 2014 indicates that the efficacy of tramadol (monotherapy) is questionable. This appears to be primarily founded on 1 meta-analysis by Chung et al. (2013), which is seriously flawed. In addition, the WHO report suggests that tramadol is different from other analgesics, because evidence supporting its use for more than 3 months is limited. A formal proof of efficacy against placebo for more than 3 months is also missing for other analgesic compounds, including paracetamol, NSAIDs, Cox-II inhibitors, weak opioids, and strong opioids. However, the long-term use of tramadol in chronic pain conditions is clinically well established (Schug 2007).

Evidence on dependence and abuse potential Tramadol has a well-characterized low abuse potential, both in pre-clinical and clinical models.

Magnitude of the problem in countries (e.g., misuse, illicit production, smuggling) In line with this low abuse potential, also low abuse levels of tramadol containing products worldwide were consistently shown in post-authorization experience for decades with high market penetration in more than 100 countries. 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, as also outlined in the recent International Narcotics Control Board survey (INCB 2014), 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. This requires the implementation of targeted local measures to stop illegal activities in these countries. The recent INCB annual report states that “tramadol is controlled in most countries where it has been found to




be abused and that a number of other countries that have encountered problems with such abuse are considering taking that measure”. Furthermore it is highlighted that “it is important to ensure that tramadol is available for medical purposes but that it is equally important for countries to ensure that it is not used for non-medical purposes” (INCB 2014).

Impact of scheduling International control of tramadol would unnecessarily adversely affect the availability of tramadol for medical purposes in many countries worldwide that are not in need of further controls. In addition it is important to stress that tramadol is in many countries the only available stronger analgesic for patients suffering from moderate to severe pain. Therefore, an unwarranted scheduling of tramadol would contribute to worsening of the existing under-treatment of pain and lead to needless suffering of pain patients, especially in developing countries. As outlined in the recent INCB survey (INCB 2014), 72% (33 of 46 countries) of the responders to this specific question of a survey have concerns that the introduction of control measures for tramadol would limit accessibility and make doctors more reluctant to prescribe the drug. This is further supported by pain societies and pain experts who have indicated that international control would significantly reduce tramadol’s availability in clinical practice, particularly in the Latin and Central American region and the Asia Pacific region.

Conclusions Grünenthal is convinced that the available data continue to support the conclusion that tramadol should not be placed under international control to enable a national decision on required measures to achieve an appropriate balance between effective minimization of abuse and ensuring availability for medical purposes.

2 DETAILED COMMENTS AND SUPPORTIVE INFORMATION

2.1 Evidence of analgesic effect of tramadol Tramadol is authorized for moderate to (moderately) severe pain in more than 100 countries worldwide.

As a result of its multiple modes of action, tramadol could be shown to be efficacious in a wide range of conditions with moderate to severe acute and chronic pain (Grond and Sablotzky 2004). In more than 25 double-blind, single and multiple dose clinical trials by Grünenthal and their licensees, the efficacy of tramadol monotherapy has been shown in post-operative pain, dental pain, pain due to trauma, abdominal pain and labor pain. A pooled analysis of 9 of the single-dose trials in post-operative pain concluded that the efficacy of tramadol monotherapy is superior to placebo (Moore and McQuay 1997). There was a clear dose response for tramadol: tramadol 100 mg had a number-needed-to-treat of 4.8 (95% confidence interval: 3.4-8.2) and tramadol 150 mg had 2.4 (2.0-3.1). For comparison: aspirin/codeine and paracetamol/propoxyphene combinations had 3.6 (2.5 6.3) and 4.0 (3.0 5.7), respectively. This suggests a stronger efficacy for tramadol monotherapy (Moore and McQuay 1997).

Between 1989 and 2005, Grünenthal (including license partners) conducted 18 double-blind trials of tramadol monotherapy in conditions associated with chronic non-cancer pain, including osteoarthritis, chronic low back pain, neuropathic pain, and fibromyalgia. The treatment durations in these trials varied from single-doses to 3 months. Nine of the 11 placebo-controlled trials,




including those with a 3-month treatment duration, showed superiority of tramadol over placebo. In the active-controlled trials, the efficacy of tramadol was not different from that of codeine, pentazocine, or dextropropoxyphene. In general, the efficacy of tramadol monotherapy is superior to that of NSAIDs at the recommended dose but is less than that of strong opioids (Lehmann 1997). Therefore, tramadol has been recommended by the WHO as a step 2 analgesic (WHO 1996) for more than 20 years.

A search in scientific literature yielded more than 350 randomized, controlled clinical trials with tramadol as monotherapy. Approximately 100 of these trials were conducted by pharmaceutical companies. The remaining trials have been conducted by independent investigators and aimed to evaluate the use of tramadol in clinical situations that were not studied by industry as part of their registration or profiling package.

Two Cochrane meta-analyses that specifically evaluated tramadol concluded that tramadol is efficacious in neuropathic pain (Duehmke et al. 2006) and pain related to osteoarthritis (Cepeda 2006). Two more Cochrane meta-analyses included tramadol in their evaluation of opioids for chronic low back pain (Chaparro et al. 2013) and rheumatoid arthritis (Whittle et al. 2011). The former meta-analysis concluded that tramadol (in 5 trials with altogether 1378 subjects) was superior to placebo for pain and function. The latter meta-analysis concluded that treatment of patients with rheumatoid arthritis with weak opioids (including tramadol) for up to 6 weeks may offer clinically-relevant improvement in pain, although adverse effects may limit the utility of weak opioids. Of note, this meta-analysis also concluded that there is insufficient evidence for the use of strong opioids for any duration in rheumatoid arthritis.

National and supranational pain societies issued evidence-based treatment guidelines recommending the use of tramadol, e.g., in neuropathic pain (Attal et al. 2010), acute and chronic low back pain (Chou et al. 2007), and osteoarthritic pain (Schnitzer et al. 2002).

The central position in pain management worldwide is also reflected by the inclusion of tramadol in various ‘Lists of Essential Medicines’. A few examples are:

• Médecins sans Frontière list of essential medicines (Pinel et al. 2013) • The International Association for Hospice & Palliative Care list of essential medicines

2007 (De Lima et al. 2007) • 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 2001b).

Section-specific comments In spite of the available convincing evidence, the WHO Tramadol Update Review Report 2014 indicates that the efficacy of tramadol (monotherapy) is questionable. This appears to be primarily founded on 1 meta-analysis by Chung et al. (2013), which is seriously flawed. A Letter to the Editor is in press demonstrating that a recalculation with correct data unequivocally shows efficacy for tramadol monotherapy (for details see Grünenthal supplemental data for WHO 2014, Section 4.1.1, Comment 4). The quotation from Radbruch (2013) that “tramadol monotherapy does not usually provide sufficient analgesia in moderate to severe pain” has major limitations. It finds its origin in




Macintyre (Macintyre et al. 2010) who cited Thévenin (Thévenin et al. 2008). The latter found that a single intravenous dose of 100 mg tramadol HCl was insufficient to relieve pain in 80% of 48 patients after moderately painful surgery. Based on this single administration data under specific conditions, it cannot be concluded that in general tramadol in monotherapy does not provide sufficient analgesia.

Quotations in the WHO Tramadol Update Review Report 2014 of other meta-analyses do not sufficiently distinguish between evidence and efficacy and may, therefore, be misunderstood, e.g., where Manchikanti et al. (2011b) is cited. It is acknowledged that the literature describing long-term safety and efficacy of opioids for chronic non-cancer pain is limited in terms of quantity and quality, precluding the formation of evidence-based conclusions supported by strong qualitative or stable quantitative evidence. The available evidence is weak for pain relief combined with improvement in functional status. However, in this context it needs to be emphasized that tramadol is the only drug that was shown to be effective for both pain relief and improvement of functional status. Another review by Manchikanti et al., focusing on long-term opioid management for chronic non-cancer pain, illustrated fair evidence for tramadol in managing osteoarthritis, while there was poor evidence for all other opioids that were analyzed (Manchikanti et al. 2011a).

In addition, the WHO Tramadol Update Review Report 2014 suggests that tramadol is different from other analgesics, because evidence supporting its use for more than 3 months is limited (page 15, 5th paragraph). The referenced publication by Reinecke et al. (2009) states that the efficacy of opioid and non-opioid analgesics has been shown in randomized clinical trials with durations from 3 weeks to 13 weeks and that efficacy was further investigated in uncontrolled surveillance studies of more than 3 months. It needs to be pointed out that tramadol is not explicitly mentioned in this article. This guideline focusses on the prevention of adverse effects and misuse. Furthermore, a multidisciplinary approach for the treatment of chronic pain is strongly recommended, and the principles of opioid prescription and management of risks associated with the long-term use of opioids are described.

Nevertheless, Grünenthal agrees that there is limited clinical trial evidence for the long-term efficacy of analgesics as currently valid regulatory guidelines (e.g., EMEA/CPMP/EWP/612/00, EMEA/CPMP/EWP/252/03 Rev. 1) do not require efficacy trials with analgesic drugs (against placebo) to exceed 3 months. Additionally, longer term trials without placebo control are sometimes difficult to interpret. This lack of long-term clinical trial data on efficacy holds true for all analgesics including paracetamol, NSAIDs, Cox-II inhibitors, weak and strong opioids, and does not distinguish tramadol from other analgesics.

However, the long-term use of tramadol in chronic pain conditions is clinically well established (Schug 2007).

2.2 Evidence on illicit manufacture and traffic It is acknowledged, that a limited number of countries, particularly in the African and Middle East region, apparently face substantial abuse of tramadol. As outlined in the recent INCB annual report (INCB 2014), in this region the problem of drug or substance abuse is not limited to tramadol but concerns numerous drugs and illicit substances including stimulants and opioids. The problem of drug abuse is considered to be the consequence of regionally persistent political and social instabilities as well as geographical factors. Furthermore, this situation has to be seen in the context




that the origin of the substances abused is not based on medical sources such as prescribing physicians or pharmacists but due to illicit trafficking (smuggling) of illegally manufactured substances mainly originated from China and India (INCB 2013 and INCB 2014).

This requires the implementation of targeted local measures to stop illegal activities in these countries. The recent INCB annual report states that “tramadol is controlled in most countries where it has been found to be abused and that a number of other countries that have encountered problems with such abuse are considering taking that measure” (INCB 2014).

However, local scheduling alone did not appropriately address the existing abuse situation in all countries. Therefore, as a next step, actions in the context of regional cooperation and national legislation change, policy and action plans are already under development/implementation together with international collaboration and dedicated activities of international organizations like the United Nations Office of Drugs and Crime (UNODC) and INTERPOL.

In conclusion, a consistent implementation of local/regional actions and careful monitoring of the abuse situation is regarded as appropriate in these countries rather than international control.

2.3 Impact of scheduling on the medical availability of tramadol 2.3.1 Role in clinical practice Leading pain experts and pain societies rate tramadol as an important WHO step 2 analgesic widely used in their clinical practice for acute pain and chronic cancer and non-cancer pain. Indications mentioned include: acute pain (e.g., postoperative pain, trauma, burns), labor pain, procedure-related pain, cancer pain, neuropathic pain, pain in sickle-cell disease, pain in HIV/AIDS, chronic non-cancer pain, as well as use in special population such as children. Tramadol is prescribed when paracetamol and/or NSAIDs and Cox-II inhibitors alone are not adequate and strong opioids are not yet warranted or available. The relevance of tramadol in pain management has further increased due to the serious safety issues associated with NSAIDs (gastrointestinal bleeding) or NSAIDs as well as Cox-II inhibitors (cardiovascular risks, nephrotoxicity), which limit their use in particular in chronic pain patients and the elderly. (Pain society and pain expert statements 2014).

Tramadol’s position in pain therapy is also reflected by its listing in many treatment guidelines and international essential medicines lists (Section 2.1). In over 50% of countries in the WHO national essential medical list section, tramadol is also listed as a national essential medicine or formulary medicine (WHO essential medicines selection 2014): Algeria, Argentina, Barbados, Bhutan, Botswana, Bulgaria, Burundi, Cape Verde, Chile, China, Congo, Cook Islands, Cote d’Ivoire, Croatia, Democratic Republic of Congo, Dominican Republic, Ecuador, Egypt, El Salvador, Eritrea, Gabon, Ghana, Honduras, India, Iran, Iraq, Jamaica, Jordan, Maldives, Malta, Marshall Islands, Mongolia, Montenegro, Morocco, Myanmar, Namibia, Oman, Palau, Peru, Philippines, Republic of Moldova, Rwanda, Serbia, Seychelles, Slovakia, Slovenia, South Africa, Sri Lanka, Syrian Arab Republic, Tajikistan, Thailand, the former Yugoslav Republic of Macedonia, Timor-Leste, Togo, Trinidad and Tobago, Tunisia, Ukraine, United Republic of Tanzania, Uruguay, Venezuela, Vietnam.

Tramadol is established in several clinical roles, usefully blending a reasonable, dose-related efficacy with a relative lack of respiratory depression, major organ toxicity, and a low abuse potential (Budd and Langford 1999). It has been used in medical practice over 40 years, with a cumulative patient exposure of more than 26 billion patient treatment days for tramadol containing




products worldwide until the end of 2012 (based on IMS Health Kilochem Study data, December 2012).

In developing countries, tramadol is often the only or one of the only stronger analgesics sufficiently available in the outpatient setting in developing countries. (Pain society and pain expert statements 2014; see also Grünenthal supplemental data for WHO 2014, Section 19, figures 8, 9, and 10).

2.3.2 Impact of an international control on tramadol’s medical availability Pain societies and pain experts around the world have indicated that international control would significantly reduce tramadol’s availability in clinical practice. Reasons given are multifold: regulatory and legal obstacles, limited availability of controlled drugs in pharmacies outside of hospitals, limited number of practitioners with special licenses to prescribe controlled drugs, insufficient supply, opiophobia, as well as reluctance of doctors to prescribe and patients to take controlled medicines (Pain society and pain expert statements 2014).

The negative impact of an international control on tramadol’s medical availability is further confirmed by results of a recent INCB survey (INCB 2014). In total, 72% of responders (33 of 46 countries) to the respective question in the INCB survey expressed concern that introduction of control measures would limit accessibility to tramadol and make doctors more reluctant to prescribe tramadol. This is well in line with past experience of national tramadol controls leading to reduced medical availability (WHO 2011; also Grünenthal supplemental data for WHO 2014, Section 19, Figure 11).

Today, controlled opioid analgesics are still barely available in developing countries (Seya et al. 2011; Human Right Watch 2011; Cleary et al. 2013 a-d; Duthey and Scholten 2014). 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).

Pain experts unanimously share the concern that the negative effects of an international control on tramadol’s medical availability will cause more pain patients to suffer. Developing countries will be the ones most severely affected – there scheduling has a huge impact on medical availability, controlled strong opioids are barely available and patients in these regions already suffer from severe under-treatment of pain (International Pain Summit 2011; WIP/EFIC/WSPC 2012).

3 REFERENCES

Grünenthal GmbH. Supplemental data for World Health Organization (Expert Committee on Drug Dependence) on drug dependence/drug abuse of tramadol. 10 March 2014.

3.1 Supportive statements Pain society and pain expert statements 2014. Tramadol’s role in therapy and impact of an international control on its medical availability: Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Peru, Venezuela, Austria, Denmark, France, Germany, Italy, Poland, Turkey, Australia, Korea, Japan, China, Malaysia, Thailand, Philippines, South Africa, Egypt, Nigeria.




3.2 Guidelines European Medicines Agency (EMA). Committee for Proprietary Medicinal Products for Human Use (CPMP): Note for guidance on the clinical investigation of medicinal products for the treatment of nociceptive pain. EMEA/CPMP/EWP/612/00; November 2002.

European Medicines Agency (EMA). Committee for Proprietary Medicinal Products for Human Use (CPMP): Guideline on clinical medicinal products intended for the treatment of neuropathic pain. EMEA/CPMP/EWP/252/03 Rev. 1; January 2007

World Health Organization (WHO). Cancer Pain Relief with a Guide to Opioid Availability. Geneva: World Health Organization, 1996.

World Health Organization (WHO). Ensuring balance in national policies on controlled substances. Guidance for availability and accessibility of controlled medicines. World Health Organization, 2011.

World Health Organization (WHO). Essential medicines selection. National Medicines List/Formulary/Standard Treatment Guidelines. Accessed on 04 April 2014. http://www.who.int/selection_medicines/country_lists/en/

3.3 Literature Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17 (9): 1113-e88.

Budd K, Langford R. Tramadol revisited. Br J Anaesth 1999; 82 (4): 493-95.

Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database of Systematic Reviews 2006, Issue 3.

Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC. Opioids compared to placebo or other treatments for chronic low-back pain. Cochrane Database of Systematic Reviews 2013, Issue 8.

Chou R, Huffman LH; American Pain Society; American College of Physicians. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med 2007;147 (7): 505-14.

Chung JW, Zeng Y, Wong TK. Drug therapy for the treatment of chronic nonspecific low back pain: Systematic review and meta-analysis. Pain Physician 2013; 16 (6): E685-E704.

Cleary J, Powell RA, Munene G, Mwangi-Powell FN, Luyirika E, Kiyange F, Merriman A, et al. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Africa: a report from the Global Opioid Policy Initiative (GOPI). Ann Oncol 2013a, Suppl 11: 14-23.

Cleary J, Radbruch L, Torode J, Cherny NI. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Asia: a report from the Global Opioid Policy Initiative (GOPI). Ann Oncol 2013b, Suppl 11: 24-32.

Cleary J, Silbermann M, Scholten W, Radbruch L, Torode J, Cherny NI. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in the Middle East: a report from the Global Opioid Policy Initiative (GOPI). Ann Oncol 2013c, Suppl 11: 51-9.




Cleary J, Simha N, Panieri A, Scholten W, Radbruch L, Torode J, Cherny NI. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in India: a report from the Global Opioid Policy Initiative (GOPI). Ann Oncol 2013d, Suppl 11: 33-40.

De Lima L, Krakauer EL and Lorenz K. Ensuring Palliative Medicine Availability: The Development of the IAHPC List of Essential Medicines for Palliative Care. J Pain Symptom Manage 2007; 33: 521-526.

Duehmke RM, Hollingshead J, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database of Systematic Reviews 2006, Issue 3.

Duthey B, Scholten W. Adequacy of opioid analgesic consumption at country, global, and regional levels in 2010, its relationship with development level, and changes compared with 2006. J Pain Symptom Manage 2014; 47 (2): 283-97.

Grond S, Sablotzky A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43:879-923.

Human Rights Watch. Global State of Pain Treatment - Access to Medicines and Palliative Care. United States of America 2011. pp. 1-132.

International Narcotics Control Board 2012. Report of the International Narcotics Control Board for 2012. New York: United Nations, 5 March 2013.


International Pain Summit Of The International Association For The Study Of Pain. Declaration of Montréal: declaration that access to pain management is a fundamental human right. J Pain Palliat Care Pharmacother 2011; 25 (1): 29-31.

Lehmann KA. Tramadol in acute pain. [Le tramadol dans les douleurs aiguës]. Drugs 1997; 53 (2): 25-33.

Macintyre PE, Scott DA, Schug SA, Visser EJ, Walker SM. Acute Pain Management: Scientific Evidence. 3rd Edition, Australian and New Zealand College of Anaesthetists 2010.

Manchikanti L, Ailinani H, Koyyalagunta D, Datta S, Singh V, Eriator I, Sehgal N, et al.. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Physician 2011a; 14 (2): 91-121.

Manchikanti L, Vallejo R, Manchikanti KN, Benyamin RM, Datta S, Christo PJ. Effectiveness of long-term opioid therapy for chronic non-cancer pain. Pain Physician 2011b, 14, pp. 133-156.

Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: Oral tramadol versus placebo, codeine and combination analgesics. Pain 1997; 69 (3): 287-294.

Pinel J, Weiss F and Henkel M. Essential drugs. Practical guidelines. s.l.: Médicines sans Frontières, 2013.

Radbruch L, Glaeske G, Grond S, Münchberg F, Scherbaum N, Storz E, Tholen K, et al. Topical review on the abuse and misuse potential of tramadol and tilidine in Germany. Subst Abus 2013; 34 (3): 313-20.




Reinecke H, Sorgatz H; German Society for the Study of Pain (DGSS). [S3 guideline LONTS. Long-term administration of opioids for non-tumor pain]. Schmerz 2009; 23 (5):440-7. [Article in German].

Schlaich C, Reinke A and Sevenich, C. Guidance to the International Medical Guide for Ships 3rd edition. Int Marit Health. 2009; 60: 1-2.

Schnitzer TJ; American College of Rheumatology. Update of ACR guidelines for osteoarthritis: role of the coxibs. J Pain Symptom Manage. 2002 Apr; 23 (4):S24-30

Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Ther Clin Risk Manag 2007; 3 (5): 717-23.

Seya MJ, Gelders SF, Achara OU, Milani B, Scholten WK. A first comparison between the consumption of and the need for opioid analgesics at country, regional, and global levels. J Pain Palliat Care Pharmacother 2011; 25 (1): 6-18.

Thévenin A, Beloeil H, Blanie A, Benhamou D, Mazoit JX. The limited efficacy of tramadol in postoperative patients: a study of ED80 using the continual reassessment method. Anesth Analg; 106 (2): 622-7.

Whittle SL, Richards BL, Husni E, Buchbinder R. Opioid therapy for treating rheumatoid arthritis pain. Cochrane Database of Systematic Reviews 2011, Issue 11.

World Institute of Pain, European Federation of IASP® Chapters, World Society of Pain Clinicians (WIP/EFIC/WSPC). Declaration of Miami 2012. Accessed on 21 May 2014. https://www.change.org/petitions/global-pain-physicians-families-and-officials-sign-the-declaration-of-miami.

TRAMADOL

Supplemental data for World Health Organization (Expert Committee on Drug Dependence)

on drug dependence/drug abuse of tramadol

23th May 2014

Supplemental data for WHO (ECDD) evaluation of drug dependence/drug abuse

of tramadol

Page 2 of 22 23 May 2014

TABLE OF CONTENTS

1 GENERAL PHARMACOLOGY, INCLUDING PHARMACOKINETICS AND PHARMACODYNAMICS 3

1.1.1 Analgesia 3

2 NON-MEDICAL USE, ABUSE AND DEPENDENCE 4

3 OTHER MEDICAL AND SCIENTIFIC MATTERS RELEVANT FOR A RECOMMENDATION ON THE SCHEDULING OF THE SUBSTANCE 12

4 OVERALL CONCLUSION 16

5 ADDITIONAL REFERENCES 17

APPENDIX 1: DETAILS OF CORRECTED META-ANALYSIS BY CHUNG 2013 21

LIST OF TABLES

Table 1: Change in pain intensity from baseline. Pain scale is VAS 0-100 mm for all studies. Length of follow-up is 12 weeks for all studies. SD=standard deviation; n=number of subjects; PE=primary endpoint. 21

Table 2: Results of the meta-analysis for each dataset. Heterogenity: Tau2=total amount of heterogeneity; Chi2=statistic for the test of heterogeneity; I2=ratio of total heterogeneity to total variability. Overall effect: Est=estimated value; 95%CI=95% confidence interval; Z=test statistic of no effect. Weights of each study in the meta-analysis: S1 corresponds to Peloso et al (2004); S2 to Ruoff et al (2003); S3 to Vorsanger et al (2008). 22

LIST OF FIGURES

Figure 1: Worldwide Tramadol consumption, expressed as kilograms and Patient Treatment Days for the years 1994 to 2012 (based on IMS Kilochem data 2012). 5

Figure 2: Worldwide reporting rates of abuse/addiction for tramadol – Grünenthal Global Drug Safety database 1980 to 2012. 6

Figure 3: Survey of Key Informants’ Patients Abuse Rates (per 1,000 URDD) over time – RADARS® System Opioids. 7

Figure 4: Opioid Treatment Program (per 1,000 URDD) over time – RADARS® System Opioids. 8

Figure 5: Drug Diversion Rates (per 1,000 URDD) over time – RADARS® System Opioids 9


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Figure 6: Poison Center Opioid Intentional Exposure Rates (per 1,000 URDD) over

time – RADARS® System Opioids. 10 Figure 7: College Survey Abuse Rates (per 1,000 URDD) over time – RADARS®

System Opioids 11 Figure 8: Tramadol consumption in Latin America in comparison to controlled opioids 13 Figure 9: Tramadol consumption in Africa in comparison to controlled opioids 14 Figure 10: Tramadol consumption in Asia in comparison to controlled opioids 14 Figure 11: Patient treatment days for tramadol in Egypt from 2003 until 2012 15

1 GENERAL PHARMACOLOGY, INCLUDING PHARMACOKINETICS AND PHARMACODYNAMICS

1.1.1 Analgesia Depending on country, tramadol is registered for the treatment of moderate to severe pain (most countries) or for moderate to moderately severe pain (USA). Consistent with this, the WHO guideline for the treatment of cancer pain 1996 lists tramadol as a Step 2 analgesic.

Clinical studies have confirmed that the multiple modes of action of tramadol contribute to its overall analgesic effect in men. The fact that non-opioid mechanisms are involved in the analgesic effect is supported by the observation that naloxone only partially (for approx. 30%) antagonized tramadol-induced analgesia in healthy subjects {Collart, 1993 210 /id}. In another study blockade of the noradrenergic activity of (-)-tramadol by yohimbine resulted in a 67%-78% reduction of the analgesic effect of tramadol in healthy subjects {Desmeules, 1996 269 /id}. Another study in patients using intravenous Patient Controlled Analgesia after major gynaecological surgery showed that similar amounts (in mg/hour) of racemic tramadol and (+)-tramadol, and far higher amounts of (-)-tramadol (Grond, et al., 1995) were consumed. This suggests that both enantiomers of racemic tramadol contribute to its overall analgesic activity and that the relative contributions of the multiple modes of action of tramadol depend on the pain condition treated. In addition, the data suggest a synergism between the enantiomers of tramadol.

Overall conclusion

Consistent with the evidence from the past, the most recent publications ({Chaparro, 2013 217 /id} and Chung {Chung, 2013 216 /id}, after re-analysis, Manchikanti {Manchikanti, 2011 260 /id}, (Manchikanti, et al., 2011), {Hollingshead, 2006 252 /id} and {Radbruch, 2013 20 /id}) demonstrate that tramadol is efficacious.

In clinical practice, tramadol is considered to be useful in a wide range of pain conditions with various underlying pain mechanisms. This is reflected by the numerous guidelines from professional medical societies that recommend use of tramadol, for example:

• WHO chronic cancer pain (WHO, 1996) • German Society for the Study of Pain (DGGS): Short introduction into the therapy of

cancer pain (Wirz, et al., 2011)


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• American College of Rheumatology: Recommendation for the use of non-

pharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee medical management of osteoarthritis of the hip and the knee (Hochberg, et al., 2012)

• A Joint Clinical Practice Guideline from the American College of Physicians and the American Pain Society: Diagnosis and Treatment of Low Back Pain (Chou, et al., 2007)

• Guideline group on chronic, nonspecific low back pain within the framework of the COST ACTION B13 ‘Low back pain: guidelines for its management’ issued by the European Commission, Research Directorate-General, department of Policy, Coordination and Strategy (Airaksinen, et al., 2006)

• European Federation of Neurological Societies (EFNS) guidelines on pharmacological treatment of NPP, 2010 (Attal, et al., 2010)

• Evidence-based guideline on the treatment of painful diabetic neuropathy from the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation (Bril, et al., 2011)

• Canadian guideline for safe and effective use of opioids for chronic non-cancer pain (Kahan, et al., 2011)

• The Médecins sans Frontière Clinical Guidelines 2013 (Pinel, et al., 2013) • Expert Panel Consensus Recommendations for the pharmacological treatment of acute

pain in the Middle East region (Ayad, et al., 2011) • Australian and New Zealand College of Anaesthetists and Faculty of pain medicine:

Acute pain management, scientific evidence (Australian and New Zealand College, 2013)

• Expert Panel Recommendations for the pharmacological treatment of peripheral neuropathic pain in the Middle East Region (Bohlega, et al., 2010).

The central position in pain management worldwide is also reflected by the inclusion of tramadol in various ‘Lists of Essential Medicines’. A few examples are:

• Médecins sans Frontière list of essential drugs 2013 (Pinel et al 2013) • The International Association for Hospice & Palliative Care list of essential medicines

(De Lima, et al., 2007) • International Maritime Organization: Medical chest for ocean-going merchant vessels

without a doctor on board (Schlaich, et al., 2009) • WHO The Interagency Emergency Health Kit 2011 (mentions tramadol as a practical

alternative to morphine in situations where opioids cannot be sent) (WHO, 2011).

2 NON-MEDICAL USE, ABUSE AND DEPENDENCE

Grünenthal’s Global Drug Safety database

Grünenthal performed a search in its Global Drug Safety database for abuse/addiction reports concerning tramadol containing products. The Data Lock Point for inclusion was 31-Dec-2012.

It is of utmost importance to stress that a meaningful interpretation of a given number of reports and the relative risk of abuse is not possible without knowledge of sales data (estimated patient exposure). This was already highlighted in the 21st WHO ECDD report:


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“Where a new drug is found to be subject to abuse prior to its being controlled, it is important to establish the rate of abuse among those exposed. Thus, one hundred cases of abuse under conditions of limited exposure would be of considerably greater significance than the same number under conditions of wide availability”.

Figure 1 shows the worldwide use of tramadol in tons and corresponding patient treatment days based on IMS Kilochem data. As one can see, worldwide consumption has increased from 290 tons in 2006 to 424 tons in 2012 (increase of 42%).

Figure 1: Worldwide Tramadol consumption, expressed as kilograms and Patient Treatment Days for the years 1994 to 2012 (based on IMS Kilochem data 2012).

Figure 2 shows the number of abuse/addiction reports in relation to patient exposure from 1980 to 2012 for tramadol. Reporting rates were calculated as the ratio of the number of reports in the Grünenthal Global Drug Safety database per million PTD (source: Intercontinental Marketing Services (IMS)).


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Figure 2: Worldwide reporting rates of abuse/addiction for tramadol – Grünenthal Global Drug Safety database 1980 to 2012. The worldwide reporting rates for tramadol for abuse peaked after market introduction in the USA in 1996, but overall have remained low and continue to decrease despite the substantial increase in patient exposure.

Conclusion

These data clearly show that the reporting rates of abuse/addiction for tramadol are low and remained below 0.3 since 2001 on the global level.

Researched Abuse Diversion and Addiction Related Surveillance (RADARS®)

Reporting rates may decrease over time without real reduction of the occurrence. In this context, it is important to point out that for tramadol a large proportion of the data comes from the USA. Previously, the Independent Steering Committee (ISC) and nowadays the Researched Abuse, Diversion and Addiction-related Surveillance (RADARS®) initiative engage in active case finding for tramadol and other substances. Due to the active case finding the number of tramadol reports is much higher than what it would be under normal circumstances of passive surveillance and allows for direct comparison to other drugs. The RADARS® System is designed to provide timely surveillance and monitoring data to characterize prescription drug abuse, misuse and diversion in the USA.


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Tramadol has been incorporated into the RADARS® System monitoring program after cessation of the Independent Steering Committee in 2005. The most recent data continue to indicate that tramadol abuse is low on all measures (Schneider, et al., 2009), although it is the only non-scheduled substance with µ-opioid receptor agonistic activity in the program up to Q32013.

1. Survey of Key Informants’ Patients Program This program is conducted through the Washington University (WU) School of Medicine to ascertain the number of people nationwide who might be abusing specific opioids and to describe the general characteristics of the abuse patterns. Figure 3 shows the current data for tramadol and other substances with µ-opioid receptor agonistic activity.

Figure 3: Survey of Key Informants’ Patients Abuse Rates (per 1,000 URDD) over time – RADARS® System Opioids.

When rank ordered with the RADARS® system opioids, the rates for tramadol are the lowest on an Unique Recipients of Dispensed Drugs (URDD) basis.

2. Opioid Treatment Program (OTP) The American Association for the Treatment of Opioid Dependence (AATOD) and the National Development and Research Institutes (NDRI) are working collaboratively to

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determine the prevalence of prescription opioid abuse among admissions to opioid treatment programs (OTPs) nationally, including methadone maintenance centers, and focusing on the states with the highest risk. Figure 4 shows the current data for tramadol and other substances with µ-opioid receptor agonistic activity.

Figure 4: Opioid Treatment Program (per 1,000 URDD) over time – RADARS® System Opioids.

When rank ordered with the RADARS® system opioids, the rates for tramadol are the lowest on an URDD basis.

3. Drug Diversion Program Data The Drug Diversion Program is conducted by the Center for Research on Substance Use & Health Disparities at Nova Southeastern University to determine the rates of diversion of selected prescription opioids based on case information obtained from a nationwide sample of police and regulatory agencies. Figure 5 shows the current data for tramadol and other substances with µ-opioid receptor agonistic activity.

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Figure 5: Drug Diversion Rates (per 1,000 URDD) over time – RADARS® System Opioids

When rank ordered with the RADARS® system opioids, the rates for tramadol are the lowest on an URDD basis.

4. Poison Center Network This program is conducted at the Rocky Mountain Poison and Drug Center (RMPDC) to compile information concerning targeted prescription pain medications associated with cases reported to the center and at least 40 other regional poison centers. Figure 6 shows the current data for tramadol and other substances with µ-opioid receptor agonistic activity.

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Figure 6: Poison Center Opioid Intentional Exposure Rates (per 1,000 URDD) over time – RADARS® System Opioids.

When rank ordered with the RADARS® system opioids, the rates for tramadol were among the lowest on an URDD basis.

5. College Survey Program The College Survey program is an online questionnaire which collects data from self-identified college students attending a two- or four-year college, university, or technical school at least part-time during the specified sampling period. Data are collected at the completion of the fall and spring academic semesters/quarters and at the end of the summer. Figure 7 shows the current data for tramadol and other substances with µ-opioid receptor agonistic activity.

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Figure 7: College Survey Abuse Rates (per 1,000 URDD) over time – RADARS® System Opioids When rank ordered with the RADARS® system opioids, the rates for tramadol were among the lowest on an URDD basis.

Conclusion on RADARS® data

The data obtained from the RADARS® Systems in line with the results of the independent Steering Committee ({Cicero, 1999 171 /id} and {Cicero, 2005 117 /id}) in the USA continue to support the occurrence of only low rates of abuse of tramadol. When abuse is recorded, this is predominantly confined to persons with a history of substance abuse. The introduction of tramadol to the USA market as a non-scheduled drug was based on the evidence of preclinical/clinical data and the already available post-marketing data from Europe. The reporting rate of abuse/dependence was as low as predicted at the beginning of USA marketing and decreased over time to an average of less than 1 case per 100,000 patients. In comparison, for methadone and extended-release oxycodone abuse/addiction rates of approximately 500 per 100,000 patients were documented in 2007 (Schneider, et al., 2009). Post-Authorization Safety Study in impaired Health Care Professionals In this study, 1601 impaired health care professionals in the USA were included who are a high risk/high access population for drug abuse (Knisely, et al., 2002). This program focused on persistent non-prescribed tramadol use in order to allow the deployment of appropriate interventions. 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 abuse

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liability of tramadol is low, as predicted by the low abuse potential demonstrated in the preclinical and clinical studies. Those who abused tramadol were previous abusers of opioids.

3 OTHER MEDICAL AND SCIENTIFIC MATTERS RELEVANT FOR A RECOMMENDATION ON THE SCHEDULING OF THE SUBSTANCE

Tramadol is a standard analgesic for the treatment of moderate to severe acute and chronic cancer and non-cancer pain; it is a stronger, and for many patients a safer, alternative to high-dosed Non-Steroidal Anti-Inflammtory Drugs (NSAIDs), including Cox-2 inhibitors (Coxibs), and an alternative to lower-dosed morphine, or other strong opioids. It is listed on the IAHPC list of essential medicines for palliative care (De Lima, et al., 2007) for the treatment of moderate cancer pain and is recognized as a practical alternative in situations where morphine is not available (WHO, 2011). Due to insufficient access to controlled opioids tramadol is in many countries the only available stronger analgesic for patients suffering from moderate to severe pain.

Efforts have been and are still undertaken by the INCB, the WHO and non-governmental organizations to improve the availability of controlled substances, but this problem is far from being solved.

The International Pain Summit of the International Association for the Study of Pain (IASP) (comprising IASP representatives from Chapters in 64 countries plus members in 130 countries, as well as members of the community), declared in 2010 that pain management is inadequate in most of the world, one factor being that there are severe restrictions on the availability of opioids and other essential medications, critical to the management of pain (Montréal, 2011). At the conclusion of the Summit, the delegates adopted a Declaration that Access to Pain Management is a Fundamental Human Right (Montréal, 2011).

A research initiative by the WHO found that in 2010, countries corresponding to 66% of the world population had virtually no consumption of strong opioids, 10% very low, 3% low, and 4% moderate (Duthey, et al., 2014).

The INCB noted in their 2010 report that access to opioid-based medications is non- existent or almost non-existent in many countries and regions (INCB, 2010).

The Global Opioid Policy Initiative (GOPI) evaluation of the availability and accessibility of opioids for the management of cancer pain (Cherny, et al., 2013) and the Human Rights Watch survey of palliative care experts in 40 countries (Human Rights Watch, 2011) further underline the concern of insufficient availability of strong opioids in developing countries. According to the results from the GOPI study, opioid availability continues to be critically low in most African countries, low throughout most of the Latin American and Caribbean countries, India, most countries in the Middle East and Asia (Cleary, et al., 2013a), (Cleary, et al., 2013b), (Cleary, et al., 2013c), (Cleary, et al., 2013d), (Cleary , et al., 2013e). The Human rights watch survey also found enormous unmet need for pain treatment, especially in Sub-Saharan Africa but also in Asia, Middle East, North Africa and Central America with no or far too low consumption of opioids for the existing needs. Factors that adversely affected availability were wide-spread overregulation, attitudinal, knowledge-related, economic and procurement-related issues (Human Rights Watch, 2011).


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Taking into account the widespread opiophobia in many of the countries outside of Europe and North America controlled substances tend to be simply not available any more once under increased national control even if local legal systems (in theory) would still allow prescription. Experience tells, however, that in daily practice the number of health care providers allowed to prescribe scheduled substances may decrease significantly and/ or health care providers tend to avoid the increased bureaucracy and adherence to complicated regulations. Both elements contribute to the consequence that scheduled strong opioids are hardly available to patients in many developing countries.

Today essential pain relieving drugs continue to be so poorly available in most of the world that WHO estimates that each year tens of millions of people suffer untreated moderate to severe pain, including 5.5 million terminal cancer patients and 1 million patients in the last phases of HIV/AIDS (WHO, 2009).

In relation to the barely available morphine and other controlled opioids in developing countries tramadol plays an important role. IMS Kilochem statistics for Africa, Asia and Latin America show that tramadol and tramadol-containing products are a cornerstone in the treatment of pain – this emphasizes that tramadol is often the only sufficiently available stronger analgesic in these regions (see Figure 8, Figure 9 and Figure 10).

*Fixed tramadol/paracetamol combination (37.5 mg/325 mg) Figure 8: Tramadol consumption in Latin America in comparison to controlled opioids (based on IMS Kilochem data: Brazil, Puerto Rico, Mexico, Argentina, Colombia, Venezuela, C. America, Ecuador, Chile, Peru, Uruguay).


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*Fixed tramadol/paracetamol combination (37.5 mg/325 mg) Only for a few countries in Africa IMS figures are available. The major decrease of tramadol consumption after 2009 is due to scheduling of tramadol as a narcotic in Egypt and respective hurdles to prescribe it for medical purposes. Figure 9: Tramadol consumption in Africa in comparison to controlled opioids (based on IMS Kilochem data: only available for few countries from the region - Algeria, Egypt, Fr. W. Africa, Morocco, South Africa, Tunisia).

Figure 10: Tramadol consumption in Asia in comparison to controlled opioids (based on IMS Kilochem data: Bangladesh, China Hospital, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, New Zealand, Pakistan, Philippines, Singapore, Taiwan, Thailand, Vietnam).


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Without any doubt, international control would affect the availability of tramadol in a negative way in many countries and thus restrict its legitimate therapeutic use. Egypt is a good example to show how increased national control can have a significantly negative effect on the availability for patients. Based on a national analysis of abuse situations the Egyptian government had decided to schedule tramadol in 2002 and to down-schedule again to the normal Egyptian prescription status as of 2004. In 2009 it was re-scheduled again. Based on IMS data tramadol consumption for medical use decreased significantly after scheduling in 2002. The consumption subsequently turned back to the previous level after changing the control status 2 years later and decreased again dramatically after re-scheduling in 2009 (see Figure 11). In order to put this result into perspective it is important to determine the need for opioid treatment in Egypt. Seya (Seya, et al., 2011) developed a method to calculate the need for morphine equivalents in several countries. When comparing the calculated needs for Egypt with the actual consumption of opioids, including tramadol, based on IMS data, it becomes apparent, that there is still a relevant gap in the availability of opioid analgesics for medical treatment. Even at times of peak sales for tramadol in 2007 (as shown in Figure 11) the tramadol consumption was far below the estimated need for opioid treatment in Egypt and this further decreased dramatically after scheduling of the drug.

Figure 11: Patient treatment days for tramadol in Egypt from 2003 until 2012 (based on IMS Kilochem data) Overall, an international control of tramadol would not be limited towards countries where there is a problem and moreover would negatively affect tramadol’s availability for medical use worldwide. The negative effect on tramadol’s availability would also affect many countries that do not need any further controls. This would contribute to worsening of the existing under-


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treatment of pain and lead to needless suffering of pain patients, especially in developing countries.

Conclusion

In summary, tramadol is a core standard analgesic widely used for the treatment of moderate to severe pain in a broad range of indications. On the global level abuse for tramadol is low and remained below 0.3 reports/million PTDs since 2001. A limited number of countries, particularly in Egypt/African and Middle East region, apparently face illicit trafficking and abuse of tramadol. No doubt, this requires the implementation of targeted local measures to stop illegal activities in these countries while ensuring that tramadol remains available for medical purposes. On the other hand, an international control of tramadol is not warranted, as it would unnecessarily affect many countries worldwide that are not in need of further controls. Rather in doing so, the availability of tramadol for millions of undertreated patients, especially in the developing countries, would be expected to decrease dramatically. This will lead to a worsening of the under treatment of pain given the still existing insufficient availability of stronger analgesics in many countries.

4 OVERALL CONCLUSION

The available data continue to support the conclusion that tramadol should not be placed under international control in order to enable a national decision on required measures to achieve an appropriate balance between effective minimization of abuse and ensuring availability for medical purposes.


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5 ADDITIONAL REFERENCES

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Knisely, JS, et al. 2002. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend. 2002, 68, pp. 15-22. Macintyre, PE. 2010. Acute Pain Management: Scientific Evidence. 3, 2010. Manchikanti, L, et al. 2011. Effectiveness of long-term opiod therapy for chronic non-canacer pain. Pain Physician. 2011, 14, pp. 133-156. Montréal, Declaration of. 2011. Declaration That Access to Pain Management Is a Fundamental Human Right. J Pain Palliat Care Pharmacother. 2011, 25, pp. 29-31. Osifo, OD and Aghahowa, ES. 2008. Safety profile and efficacy of commonly used analgesics in surgical neonates in Benin city, Nigeria. Am J Perinatol. 2008, Vol. 10, 25, pp. 617-622. Peloso, PM, et al. 2004. Analgesic efficacy and safety of tramadol/acetaminophen combination tablets (Ultracet ®) in treatment of chronic low back pain: a multicentre, outpatient, randomized, double blind, placebo controlled trial. J Rheumatol. 2004, 31, p. 12. Pinel, J, Weiss, F and Henkel, M. 2013. Essential drugs. Practical guidelines. s.l. : Médicines sans Frontières, 2013. Preston, KL, Jasinski, DR and Testa, M. 1991. Abuse potential and pharmacological comparison of tramadol and morphine. Drug and alcohol dependence. 1991, 27, p. 7.17. Raffa, RB, et al. 1993. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther. 1993, Vol. 1, 267, pp. 331-340. Raffa, RB, et al. 1992. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. J Pharmacol Exp Ther. 1992, Vol. 1, 260, pp. 275-285. Ren, YH and Zheng, JW. 2000. Influence of tramadol on morphine discriminative behavior in rats. Acta Pharmacol Sin. 2000, Vol. 10, 21, pp. 924-926. Richter, W, et al. 1985. Clinical investigation on the devlopment of dependence during oral therapy with tramadol. Drug Res. 1985, Vol. 2, 35, pp. 1742-1744. Ruoff, GE, et al. 2003. Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicentre, randomized, double-blind, placebo-controlled outpatient study. Clin Therapeut. 2003, 25, pp. 1123-1141. Schlaich, C, Reinke, A and Sevenich , C. 2009. Guidance to the International Medical Guide for Ships 3rd edition. Int Marit Health. 2009, 60, pp. 1-2. Schneider, MF, et al. 2009. Integrating nine prescription opioid analgesics and/or four signal detection systems to summarize statewide prescription drug abuse in the United States in 2007. Pharmacoepidemiol Drug Saf. 2009, 18, pp. 778-790. Schnitzer, TJ, et al. 2000. Efficacy of tramadol in treatment of chronic low back pain. The Journal of Rheumatology. 2000, Vol. 3, 27, pp. 772-778. Seya, MJ, et al. 2011. A first comparison between the consumption of and the need for opioid analgesics at country, regional, and global levels. J Pain Palliat Care Pharmacother. 2011, 25. Shadnia, S, et al. 2008. Tramadol intoxication: a review of 114 cases. Human & experimental toxicology. 2008, 27, pp. 201-205. Thévenin, A, et al. 2008. The limited efficacy of tramadol in postoperative patients: A study of ED80 using the continual reassesment method. International anaesthesia research society. 2008, Vol. 2, 206, pp. 622-627. Überall MA, Mueller-Schwefe GH and Terhaag B. 2012. Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study. Curr Med Res Opin. 2012, 28, pp. 1617-34. Vorsanger, GJ, et al. 2008. Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain. J Opiod Manag. 2008, 4, pp. 87-97.


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WHO. 2009. Briefing Note: Access to Controlled Medicines Program. [Online] Feb 2009. http://www.who.int/medicines/areas/quality_safety/ACMP_BrNoteGenrl_EN_Feb09.pdf. —. 2011. The Interagency Emergency Health Kit 2011: medicines and medical devices for 10 000 people for approximately three months. 2011. —. 1996. WHO. Cancer pain relief with a guide to opiod availability. Geneva : s.n., 1996. Wirz, S, Schenk, M and Emrich, O. 2011. Kurzanleitung Tumorschmerztherapie. 1. 2011. Yanagita, T. 1978. Drug dependence potential of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol hydrochloride (tramadol) tested in monkeys. Drug Res. 1978, Vol. 1a, 28, pp. 158-163.


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APPENDIX 1: DETAILS OF CORRECTED META-ANALYSIS BY

CHUNG 2013

Chung {Chung, 2013 216 /id} performed a systematic review and meta-analysis of studies published between 2002 and 2012 to assess the efficacy of several drug therapies for the treatment of chronic nonspecific low back pain.

The authors included 3 studies (Ruoff et al (2003), Vorsanger et al (2008) and Peloso et al (2004)) in their meta-analysis. Chung et al (2013) used the VAS pain intensity as primary efficacy measure for their meta-analysis for the studies by Ruoff et al (2003) and Vorsanger et al (2008). It seems that for the study by Peloso et al (2004) they used the mean and SD values for change from baseline of the SF-MPQ/present pain index instead of the VAS pain intensity which is available as well. In addition, we were unable to deduct from the study by Ruoff et al (2003) the SD-values for the change from baseline reported by Chung et al (2013).

We conducted 2 meta-analyses with datasets D1 and D2. Dataset D1 consists of data reportedly used by Chung et al (2013). Dataset D2 differs from D1 in that from the study by Peloso et al (2004) the change from baseline in VAS pain intensity has been taken and that the SD-value sC for the study by Ruoff et al (2003) was calculated in the same way as it was calculated for the other two studies as follows (Table 1):

sC = �s02 + s12 − 2rs0s1, where s0 and s1 are the observed standard deviations of pain intensity scores at baseline and end-of-treatment, respectively and r is the correlation between pain intensity scores at baseline and end-of-treatment. Since this correlation is not reported, we have assumed r = 0.8 in all studies following what Chung et al (2013) presumably did for the study of Vorsanger et al (2008). Peloso et al (2004) and Ruoff et al (2003) did not report s1; therefore we have assumed that s1 = s0.

Our results for dataset D1 are identical to those of Chung et al (2013). The results for dataset D2 showed a statistically significant difference (estimated overall effect -1.18; 95% confidence interval -1.65 to -0.71; p<0.0001) between tramadol and placebo (Table 2).

We conclude that there is persuasive evidence for a benefit of tramadol alone or in fixed dose combination with paracetamol/acetaminophen in the management of chronic low back pain. This is important to report because, in contrast to NSAIDs and Cox-II-inhibitors, long-term use of tramadol is not associated with an increased risk of (gastro-intestinal, renal and cardiovascular) organ damage and, in contrast to strong opioids, the risk of respiratory depression, addiction and abuse is lower.

Table 1: Change in pain intensity from baseline. Pain scale is VAS 0-100 mm for all studies. Length of follow-up is 12 weeks for all studies. SD=standard deviation; n=number of subjects; PE=primary endpoint.

Tramadol Placebo Dataset

Study Source Mean SD n Mean SD n D1 D2

Peloso 2004 Chung 2013 -1 1.2 167 -0.4 1.2 171 X

Peloso 2004, PE revised

-20.5 9.46 167 -4.7 9.82 169 X


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Ruoff 2003 Chung 2013 -26.7 2.66 161 -16.5 2.63 157 X

Ruoff 2003, SD revised

-26.7 9.17 158 -16.5 9.42 153 X

Vorsanger 2008

Chung 2013 -20 14.36 128 -8 14.36 129 X X

Table 2: Results of the meta-analysis for each dataset. Heterogenity: Tau2=total amount of heterogeneity; Chi2=statistic for the test of heterogeneity; I2=ratio of total heterogeneity to total variability. Overall effect: Est=estimated value; 95%CI=95% confidence interval; Z=test statistic of no effect. Weights of each study in the meta-analysis: S1 corresponds to Peloso et al (2004); S2 to Ruoff et al (2003); S3 to Vorsanger et al (2008).

Heterogeneity Overall effect Weights (%)

Dataset Tau2 Chi2 (df)

p-value I2 Est.

(95%CI)

Z p-value S1 S2 S3

D1 2.32 243.5 (2)

<0.0001 99.18% -1.72

(-3.45, 0.01)

-1.95

0.0518 33.5 33.1 33.4

D2 0.156

21.67 (2)

<0.0001

90.77%

-1.18

(-1.65,-0.71)

-4.94

<0.0001 33.32

33.54

33.14

of 5

TRAMADOL

Comments to the World Health Organization (WHO; Expert Committee on Drug Dependence)

Tramadol Expert Peer Review Report No. 1

Prepared by:

Grünenthal GmbH, Germany

Submitted by:

International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Switzerland

for the World Health Organization

26 May 2014


WHO (ECDD) Tramadol Expert Peer Review Report No. 1

Page 2 of 5 26 May 2014

COMMENTS TO THE PEER REVIEW REPORT NO. 1 ON TRAMADOL

Grünenthal is convinced that the available data continue to support the conclusion that tramadol should not be placed under international control to enable a national decision on required measures to achieve an appropriate balance between effective minimization of abuse and ensuring availability for medical purposes. The conclusion of the peer reviewer to place tramadol under schedule IV of the 1971 convention is based on assumptions which do not reflect the actual body of evidence. This is mainly an underestimation of the efficacy of tramadol, an overestimation of the worldwide abuse levels and an underestimation of the adverse impact of scheduling.

Evidence on dependence and abuse potential Tramadol has a well-characterized low abuse potential, both in pre-clinical and clinical models.

Risks to individual and society because of misuse As stated in the Update WHO Review Report, tramadol is considered to be a relatively safe analgesic. At therapeutic doses, tramadol does not cause clinically relevant respiratory depression. Fatal intoxications are rare and appear to be associated with large overdoses of tramadol and co-ingestion of other drugs (including alcohol).

Magnitude of the problem in countries (misuse, illicit production, smuggling etc) In line with this low abuse potential, also low abuse levels of tramadol containing products worldwide were consistently shown in post-authorization experience for decades with high market penetration in more than 100 countries. 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, as also outlined in the recent International Narcotics Control Board survey (INCB 2014), 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.

This requires the implementation of targeted local measures to stop illegal activities in these countries. The recent INCB annual report states that “tramadol is controlled in most countries where it has been found to be abused and that a number of other countries that have encountered problems with such abuse are considering taking that measure”. Furthermore it is highlighted that “it is important to ensure that tramadol is available for medical purposes but that it is equally important for countries to ensure that it is not used for non-medical purposes” (INCB 2014).

Need of the substance for medical practice Tramadol is authorized for moderate to (moderately) severe pain in more than 100 countries worldwide. Leading pain experts and pain societies rate tramadol as an effective WHO step 2 analgesic widely used in their clinical practice for acute pain and chronic cancer and non-cancer pain. (Pain society and pain expert statements 2014)

The efficacy of tramadol has been established based on more than 350 randomized, controlled, clinical trials, conducted by pharmaceutical industry or by independent investigators in a wide range of indications with moderate to severe acute and chronic pain. Particularly, the efficacy of tramadol monotherapy has been shown in various acute and chronic pain models including post-operative pain, dental pain, pain due to trauma, abdominal pain, labor pain, as well as cancer pain, pain due to osteoarthritis, chronic low back pain, neuropathic pain, and fibromyalgia.



Page 3 of 5 26 May 2014

Also, tramadol is recommended by the WHO as a step 2 analgesic (WHO 1996).

Meta-analyses by Cochrane and others as well as evidence based treatment recommendations by pain societies worldwide provide support that tramadol is an efficacious, versatile and useful analgesic, particularly in situations where paracetamol, NSAIDs and cyclooxygenase (Cox)-II inhibitors provide insufficient analgesia, are not tolerated, or are contra-indicated, and where there is hesitation to use strong opioids.

In spite of the available convincing evidence, the WHO Tramadol Update Review Report 2014 indicates that the efficacy of tramadol (monotherapy) is questionable. This appears to be primarily founded on 1 meta-analysis by Chung et al. (2013), which is seriously flawed. In addition, the WHO report suggests that tramadol is different from other analgesics, because evidence supporting its use for more than 3 months is limited. A formal proof of efficacy against placebo for more than 3 months is also missing for other analgesic compounds, including paracetamol, NSAIDs, Cox-II inhibitors, weak opioids, and strong opioids. However, the long-term use of tramadol in chronic pain conditions is clinically well established (Schug 2007).

Measures taken by countries to curb misuse The recent INCB annual report states that “tramadol is controlled in most countries where it has been found to be abused and that a number of other countries that have encountered problems with such abuse are considering taking that measure” (INCB 2014).

Impact of if substance is scheduled As outlined in the recent INCB survey (INCB 2014), 72% (33 of 46 countries) of the responders to this specific question of a survey have concerns that the introduction of control measures for tramadol would limit accessibility and make doctors more reluctant to prescribe the drug. This is further supported by pain societies and pain experts who have indicated that international control would significantly reduce tramadol’s availability in clinical practice, particularly in the Latin and Central American region and the Asia Pacific region. (Pain society and pain expert statements 2014).

Other comments or opinions Absence of Evidence regarding Suicide risk associated with Tramadol The FDA decided to update the tramadol label related to a risk of suicide. Grünenthal is of the opinion that there is no sufficient evidence to suggest that tramadol may be associated with the risk of suicidal behavior. This was confirmed by the European Pharmacovigilance Working Party. In the Assessment Report on tramadol published in July 2012 the PhVWP concluded the following: ‘The PhVWP agreed that the present data did not support a causal relationship between tramadol and suicidal ideation or behaviour. […] The PhVWP therefore concluded that a warning regarding the use of tramadol in patients who are suicidal, suffering from emotional disturbances or depression, as introduced in the US prescribing information in 2010, was disproportionate at this time, also considering that other medicines with potential for suicide do not carry a similar warning and that there was no evidence that tramadol is used more frequently in suicidal acts.’ (PhVWP 2012).



Page 4 of 5 26 May 2014

Conclusions Therefore, Grünenthal is convinced that the available data continue to support the conclusion that tramadol should not be placed under international control to enable a national decision on required measures to achieve an appropriate balance between effective minimization of abuse and ensuring availability for medical purposes.



Page 5 of 5 26 May 2014

1 REFERENCES

1.1 Supportive statements Pain society and pain expert statements 2014. Tramadol’s role in therapy and impact of an international control on its medical availability: Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Peru, Venezuela, Austria, Denmark, France, Germany, Italy, Poland, Turkey, Australia, Korea, Japan, China, Malaysia, Thailand, Philippines, South Africa, Egypt, Nigeria.

1.2 Literature Chung JW, Zeng Y, Wong TK. Drug therapy for the treatment of chronic nonspecific low back pain: Systematic review and meta-analysis. Pain Physician 2013; 16 (6): E685-E704.


Pharmacovigilance Working Party (PhVWP). Summary Assessment Report of the PhVWP July 2012: Tramadol – Risk of adverse reactions of the central-nervous system and dosing in the elderly and those with renal or liver impairment. EMA/CHMP/PhVWP/438980/2012, PhVWP Monthly report on safety concerns, guidelines and general matters July 2012, Annex 9.

Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Ther Clin Risk Manag 2007; 3 (5): 717-23.

World Health Organization (WHO). Cancer Pain Relief with a Guide to Opioid Availability. Geneva: World Health Organization, 1996.

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