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Cross-Sectional Pilot Study to Monitor the Availability, Dispensed Prices, and Affordability of Opioids Around the Globe

Open AccessPublished:April 04, 2014DOI:https://doi.org/10.1016/j.jpainsymman.2013.12.237

      Abstract

      Context

      Opioids are essential medicines. The World Health Organization and Health Action International monitor the price of essential medicines. However, their surveys do not include opioids, and there is no information on their affordability.

      Objectives

      To provide information on access to pain treatment, as measured by the availability and dispensed price of five opioids in 13 formulations, and the affordability of oral immediate-release (IR) morphine.

      Methods

      The International Association for Hospice and Palliative Care members were distributed by their countries' Gross National Income (GNI) level using the World Bank categories, i.e., high income country (HIC), upper middle income country (UMIC), lower middle income country (LMIC), low income country (LIC), and randomized. A total of 10 participants were selected from each (n=40) domain. Participants were asked to identify a pharmacy located closest to a public facility that provides diagnosis/treatment for life-threatening conditions and report the lowest dispensed price of the smallest selling unit and strength of each formulation. Availability and median (Me) price were calculated for each. Affordability and percentage of international buyer price (IBP) were calculated for morphine oral solid IR.

      Results

      A total of 30 participants from 26 countries (response rate=75%) responded. Significant correlation was found between availability and GNI (range: 65–68% [HIC and LIC]; R=0.781; P<0.0001). Injectable and morphine oral solid sustained release (SR) were the most available (59% and 55%). Methadone (oral) was the least expensive (Me=0.5) followed by fentanyl (transdermal; Me=2.2). The Me price for morphine oral solid IR and ratios between dispensed and IBP were lower in HIC than in LMIC (price=0.03 vs. 0.16; ratio=2.23 vs. 0.03). Affordability for morphine oral solid IR was five days (Me=0.1; range=29–0.25).

      Conclusion

      Patients in LMIC and LIC have limited access to opioids, and there are subsidies in place for more expensive medications and formulations in all GNI levels, but not for morphine oral solid IR. Additional research is necessary to identify the reasons behind these findings.

      Key Words

      Introduction

      The World Health Organization (WHO) recognizes palliative care and pain relief as critical public health issues.
      • Davies E.
      • Higginson I.
      The solid facts: Palliative care.
      World Health Organization (WHO)
      National Cancer Control Programs: Policies and Managerial Guidelines.
      World Health Organization (WHO)
      Access to Controlled Medicines Programme (ACMP)—Framework.
      Strong opioids are a cornerstone of pain treatment, of which morphine is considered essential by the WHO.
      World Health Organization (WHO)
      Model List of Essential Medicines.
      In 2007, the International Association for Hospice and Palliative Care (IAHPC) developed a list of Essential Medicines (EMLs) in Palliative Care,
      • De Lima L.
      • Krakauer E.L.
      • Lorenz K.
      • Praill D.
      • Macdonald N.
      • Doyle D.
      Ensuring palliative medicine availability: the development of the IAHPC list of essential medicines for palliative care.
      which includes opioids for the treatment of pain and other symptoms. Still, in many countries, limited or no access is a significant problem. Developing countries with about 80% of the world population account for 6% of the global morphine consumption
      World Health Organization (WHO)
      Access to Controlled Medicines Programme (ACMP)—Framework.
      resulting in millions of patients suffering needlessly.
      Access to opioids is limited owing to several reasons, including restrictive drug control laws and regulations, lack of education, and high prices.
      • Cherny N.I.
      • Baselga J.
      • de Conno F.
      • Radbruch L.
      Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative.
      • Joranson D.E.
      Availability of opioids for cancer pain: recent trends, assessment of system barriers, New World Health Organization guidelines, and the risk of diversion.
      In developing countries, they have been reported to be more expensive than in developed nations,
      • Bruera E.D.
      • De Lima L.
      Opioid cost: a global problem.
      • De Conno F.
      • Ripamonti C.
      • Brunelli C.
      Opioid purchases and expenditure in nine western European countries: “are we killing off morphine?”.
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      • Palmer J.L.
      • Bruera E.
      Potent analgesics are more expensive for patients in developing countries: a comparative study.
      • Craig B.M.
      • Strassels S.A.
      Out-of-pocket prices of opioid analgesics in the United States, 1999-2004.
      and prices in small cities and rural areas are higher than in large cities.
      • Wenk R.
      • Bertolino M.
      • De Lima L.
      Analgésicos opioides en Latinoamérica: la barrera de accesibilidad supera la de disponibilidad [Opioid analgesics in Latin America: the barrier of accessibility in higher than disponsibility].
      Opioid pricing is impacted by additional factors, such as markups resulting from safety and security measures required by the national laws on the manufacturing, importation, distribution, storage, and dispensation of controlled medicines. Pricing is also affected by the type of formulation, namely complex delivery mechanisms, such as transdermal patches (TPs); transmucosal or SR formulations are costlier to make than immediate release (IR) oral formulations (solid or liquid).
      The WHO and Health Action International (HAI) developed a method to monitor and report the price of essential medicines as a measure of access,

      World Health Organization, Health Action International. Measuring medicine prices, availability, affordability and price components 2008. Available from: http://www.who.int/medicines/areas/access/OMS_Medicine_prices.pdf. Accessed July 14, 2013.

      which has prompted some governments to lower the cost of medicines.
      • Mendis S.
      • Fukino K.
      • Cameron A.
      • et al.
      The availability and affordability of selected essential medicines for chronic diseases in six low- and middle-income countries.
      However, with one exception,
      • Poltavets D.
      • Konovalova L.
      Medicine prices, availability, affordability & price components.
      the WHO/HAI surveys do not include opioids, and there is limited information on their price and affordability. In 2008, the IAHPC decided to develop the Opioid Price Watch (OPW) Project as a component of the agreement of work as a nongovernmental organization in formal relations with the WHO. This article describes the pilot study implemented to test the OPW.

      Objectives

      The objectives of the article are to:
      • 1.
        Provide information on opioid availability globally;
      • 2.
        Show opioid price patterns among regions and countries, as reflected in differences in treatment costs, affordability, and differences in prices as a ratio of the international reference price; and
      • 3.
        Allow further analysis of the difficulties in availability and affordability of opioid analgesics and suggest possible strategies addressing the identified problems.

      Methods

      The study design was a cross-sectional study.

      Strengthening the Reporting of Observational studies in Epidemiology (STROBE). Checklist for cross-sectional studies 2009. Available from: http://www.strobe-statement.org/index.php?id=available-checklists. Accessed August 30, 2013.

      The project proposal is available on the IAHPC web site in http://hospicecare.com/resources/opioid-price-watch/. An ethics review board from the Fundacion Federacion Medica de Buenos Aires in Argentina approved the study.
      The opioids were selected using the following criteria:
      The following medications and formulations were selected.
      • 1.
        Fentanyl TPs
      • 2.
        Hydromorphone (injectable, oral liquid, oral solid IR, and oral solid SR)
      • 3.
        Methadone (oral liquid and oral solid)
      • 4.
        Morphine (injectable, oral liquid, and oral solid [IR and SR])
      • 5.
        Oxycodone (oral solid IR and SR)
      All member states of the United Nations report consumption of these medications to the International Narcotics Control Board.
      International Narcotics Control Board (INCB)
      Annual Report. Report of the International Narcotics Control Board for 2009.
      The study sample was selected using the IAHPC members' list following a stratified random sampling:
      • 1.
        The IAHPC members were listed by country in alphabetical order.
      • 2.
        Countries were stratified by their Gross National Income (GNI) using the World Bank categories: low income countries (LICs), low middle income countries (LMICs), upper middle income countries (UMICs), and high income countries (HICs).

        World Bank. How we classify countries 2011. Available from: http://data.worldbank.org/about/country-classifications. Accessed July 14, 2013.

      • 3.
        The IAHPC members were listed by their corresponding country's GNI and each list was randomized.

        Haahr M. List Randomizer: Randomness and Integrity Services Ltd.; 1998 Available from: http://www.random.org/. Accessed September 22, 2011.

      • 4.
        The first 10 participants in each category were selected, resulting in 40 potential participants.
      Selected individuals were contacted by e-mail and invited to participate. Whenever one declined the invitation or if he/she did not reply, the next individual in the list was invited.
      Participants were informed of the objectives of the study, total estimated time to complete the survey, that their names would be acknowledged, and that the data presented would be linked to their countries. A signed informed consent was submitted by all before completing the survey. Participants were asked to select the pharmacy located closest to a public health facility that provides diagnostic and treatment services for patients with life-threatening conditions. They were asked to speak to the chief pharmacist. A letter describing the project and identifying them as participants of the study was shown to the pharmacist. Participants were instructed to inquire if at least one of the opioids included in the study was available and dispensed for ambulatory patients. If opioids were not available or the pharmacist was unwilling to cooperate, they were asked to go to the next nearest pharmacy and to continue this process until they located one pharmacy that had at least one opioid available and where the chief pharmacist was willing to collaborate. Participants were asked to record in their local currency the lowest retail dispensed price of the smallest selling dose and unit for the opioid formulations available on the day they completed the survey. The address of the surveyed pharmacy was also recorded to avoid potential duplication. The Appendix (available at jpsmjournal.com) includes a sample of the survey form. The completed survey was submitted via the IAHPC server http://hospicecare.com/opioids/reports/add. Data were collected from September 2012 to April 2013. Prices were converted to U.S. Dollars (USD) using Google Finance Converter.

      Google Finance Converter. Available from: http://www.google.com/finance/converter Accessed April 10, 2012.

      Survey results were exported to Microsoft Excel and IBM SPSS Statistics 21.

      Definitions

      The following definitions were applied in the study:

      World Health Organization, Health Action International. Measuring medicine prices, availability, affordability and price components 2008. Available from: http://www.who.int/medicines/areas/access/OMS_Medicine_prices.pdf. Accessed July 14, 2013.

      Accessibility: The extent that patients can obtain the opioid medications they need for pain relief—patient access is not possible unless opioids are available and affordable.
      Affordability: Total number of days required by a patient earning the minimum wage to purchase a 30-day treatment of medications at the dispensed price.

      World Health Organization. Collaborating Center for Drug Statistics Methodology. ATC/DDD Index 2011 2011. Available from: http://www.whocc.no/atc_ddd_index/. Accessed April 24, 2011.

      Availability: Existence of the opioid medication in stock at the pharmacy to be dispensed to patients arriving at the pharmacy with a legitimate medical prescription. It was calculated by the percentage of opioids available at the moment the survey was completed, with 13 being the maximum number of formulations. The amount of pharmacies visited before finding one that had any of the opioids included in the study was recorded.
      Dispensed Price: Pharmacy selling price plus any fees and any sales taxes. Dispensed price for a 30-day treatment for each medication was calculated by dividing the price of the package/bottle by the total milligrams in each, and then multiplying the resulting price per milligram by the corresponding monthly treatment of the Defined Daily Dose (DDD;

      World Health Organization, Health Action International. Measuring medicine prices, availability, affordability and price components 2008. Available from: http://www.who.int/medicines/areas/access/OMS_Medicine_prices.pdf. Accessed July 14, 2013.

      Table 1). The DDD is the average maintenance dose per day for a drug used for its main indication in adults established by the WHO Collaborating Center for Drug Statistics Methodology.

      Wikipedia. List of minimum wages by country 2012. Available from: http://en.wikipedia.org/wiki/List_of_minimum_wages_by_country Accessed April 15, 2012.

      • Walker P.W.
      • Palla S.
      • Pei B.L.
      • et al.
      Switching from methadone to a different opioid: what is the equianalgesic dose ratio?.
      The DDD is a quantitative measure for statistical purposes only and not to be used as a treatment guideline.
      Table 1Amount Needed for a 30-Day Treatment for Each Medication
      Medication—FormulationDDD (mg)30-Day Treatment (DDD×30)

      World Health Organization. Collaborating Center for Drug Statistics Methodology. ATC/DDD Index 2011 2011. Available from: http://www.whocc.no/atc_ddd_index/. Accessed April 24, 2011.

      Fentanyl—transdermal0.001236
      Hydromorphone—oral20600
      Hydromorphone—injectable4120
      Morphine—oral (IR and SR)1003000
      Morphine—injectable30900
      Oxycodone—oral752250
      Methadone—oral
      Given that there is no identified DDD for pain treatment with methadone, a morphine equivalent dose was defined as 1:5 based on the published literature:22 (100 mg/5=20 mg).
      20600
      DDD=Defined Daily Dose; IR=immediate release; SR=sustained release.
      a Given that there is no identified DDD for pain treatment with methadone, a morphine equivalent dose was defined as 1:5 based on the published literature:

      Wikipedia. List of minimum wages by country 2012. Available from: http://en.wikipedia.org/wiki/List_of_minimum_wages_by_country Accessed April 15, 2012.

      (100 mg/5=20 mg).
      Median (Me) Price: The middle value in a distribution, above and below which lie an equal number of the highest and lowest prices recorded for each medication.
      Median Price Ratio (MPR): Difference between the reported dispensed price and the international buyer reference price given by the International Drug Price Indicator Guide.

      Management Sciences for Health (MSH). International Drug Price Indicator Guide 2011. Available from: http://erc.msh.org/Accessed April 21, 2012.

      Data Analysis

      This article presents results and analysis of the following data:
      • 1.
        For five opioids in 13 formulations: availability, dispensed price of lowest dosage available, and Me price of each.
      • 2.
        For morphine oral solid IR: In addition to the Dispensed price, the MPR and Affordability were also calculated for this medication and formulation. The reason is that morphine oral solid IR has been used as a reference for monitoring consumption of opioids, and it is included as the gold standard essential strong analgesic in the WHO Model EMLs.
        World Health Organization (WHO)
        Model List of Essential Medicines.
      A descriptive analysis of the data and a comparative analysis by GNI region were conducted. Given the sample size, Spearman's rank correlation coefficients (Rs) and Kruskal-Wallis tests were used when applicable.

      Results

      Data were submitted by 30 participants from 26 countries (75% response rate). Participants are listed in the Acknowledgment section. Reports were submitted from two locations in two countries, namely China (Beijing and Chengdu) and the U.K. (Edinburgh and Leeds); whereas reports from three locations were submitted from Tanzania (two in Arusha and one in Dar es Salaam). Reports from Arusha (Arusha 1 and 2) were the same for availability and prices. In Chile and Poland, the survey was submitted by the invited participant and an additional collaborator, not included in the response rate but listed in the Acknowledgment section.

      Availability

      The average number of pharmacies visited before finding the one that had at least one of the opioids included in the study varied by GNI: HIC: 1 (range=0–1, Me=0.6), UMIC: 1 (range=0–2, Me=1), LMIC: 9 (range=1–40, Me=2.5), and LIC: 4.5 (range=3–15, Me=6.1). In Moldova, Nepal, and Sudan, opioids are available only in hospital pharmacies allowed to dispense for nonhospitalized patients.
      Availability of opioid formulations ranged from 11 (85%) in Norway to 0 in Kenya, Nigeria, Tanzania (Dar es Salaam), and Uganda. In five locations (Bangladesh, Brazil, Ethiopia, Tanzania [Arusha 1 and 2], and Uruguay), only one opioid was available, followed by Moldova with two. Norway had the highest number available,
      • Craig B.M.
      • Strassels S.A.
      Out-of-pocket prices of opioid analgesics in the United States, 1999-2004.
      followed by Germany, New Zealand, and Spain.
      • De Conno F.
      • Ripamonti C.
      • Brunelli C.
      Opioid purchases and expenditure in nine western European countries: “are we killing off morphine?”.
      The mean percentage of medications available is strongly related to GNI level, ranging from 65% to 8% (HIC and LIC, respectively; Table 2). A significant positive correlation between the country's GNI and the availability of opioids was found (Rs=0.781; P<0.0001). In all HIC, availability was higher than 50%, with the exception of Poland (46%). Brazil and Uruguay had the lowest availability in the UMIC group (8%), whereas the highest availability was in China (Chengdu) and Romania (almost 50%). The extremes of the LMIC groups were Guatemala and Nigeria (62% and 0%, respectively). Nepal stands out in the LIC group with 31% of the medications available.
      Table 2Availability of Opioids by Income Groups
      Income Group (GNI)Mean Percent
      Spearman's rank correlation coefficient (Rs)=0.781; P<0.0001, Kruskal-Wallis tests P<0.0001.
      Country (City)% Of Opioids Available
      HIC64.8Norway (Bergen)84.62
      Germany (Aachen)69.23
      New Zealand (Wellington)69.23
      Spain (Pamplona)69.23
      U.K. (Leeds)61.54
      U.K. (Edinburgh)53.84
      Poland (Poznan)46.15
      UMIC29.1China (Chengdu)46.15
      Romania (Brasov)46.15
      Chile (Santiago)38.46
      Iran (Teheran)38.46
      Argentina (San Nicolas)30.77
      China (Beijing)23.08
      Russia (Kemerovo)23.08
      Brazil (Rio de Janeiro)7.69
      Uruguay (Montevideo)7.69
      LMIC28.2Guatemala (Guatemala City)61.54
      Philippines (Iloilo City)38.46
      India (New Delhi)30.77
      Sudan (Khartoum)23.08
      Moldova (Chisinau)15.38 Nigeria (Ibadan)
      LIC7.7Nepal (Bharatpur)30.77 Bangladesh (Dhaka)
      Ethiopia (Hawassa)7.69
      Tanzania (Arusha 1)7.69
      Tanzania (Arusha 2)7.69
      Tanzania (Dar es Salaam)0
      Kenya (Nairobi)0
      Uganda (Kampala)0
      GNI=Gross National Income; HIC=high income country; UMIC=upper middle income country; LMIC=lower middle income country; LIC=low income country.
      a Spearman's rank correlation coefficient (Rs)=0.781; P<0.0001, Kruskal-Wallis tests P<0.0001.
      Injectable morphine (ampoule) was the most available (58%, n=17), followed by morphine oral solid SR (53%, n=16), then by morphine oral solid IR, fentanyl TP, and oxycodone SR (47%, n=14). Morphine ampoule was available in three of the LIC (Bangladesh, Ethiopia, and Nepal), whereas morphine liquid was available in Nepal and Tanzania (Arusha 1 and 2). No opioids were available in Kenya, Nigeria, Tanzania (Dar es Salaam), or Uganda, but none reported that the opioids were never available. Hydromorphone was the least available of all: liquid (none), ampoule (China [Beijing]), IR solid (Norway and China [Beijing]), and SR solid (Germany, Norway, and Spain).

      Dispensed Prices

      Opioids are dispensed free in Chile, Moldova, Nepal, New Zealand, Russia, Sudan, and Tanzania (Arusha 1 and 2). In Edinburgh, opioids are free, but not in Leeds (U.K.). In Germany, medications are dispensed at no cost to the patients through a health insurance fund, but patients are required to pay a fixed dispensing fee.
      The Me price for morphine oral solid IR 10 mg ranged between USD 0.03 and 0.16 for HIC and LMIC, respectively, whereas the MPR ranged between USD 0.06 and 0.33 in HIC and LMIC, respectively (Table 3). Table 4 describes the Me price comparison of a 30-day treatment by GNI. The Me price of 30-day treatment of morphine oral solid IR 10 mg was less in HIC (USD 4.6) than in lower GNI groups (UMC=30.5 and LM=46.8). Apart from morphine liquid, which is free in seven of 13 countries (Me=0), methadone oral solid was the lowest-priced medicine (Me=0.5), followed by fentanyl TP (Me=2.2). Synthetic opioids and in some cases opioids with more complex delivery mechanisms (TP and oral SR) were dispensed at lower prices than morphine oral solid IR. Fentanyl TP is free in Chile, Iran, New Zealand, Romania, and Russia and the least expensive in Germany, Guatemala, India, Norway, Philippines, Poland, Spain, and the U.K. (Leeds). In general, it was found that if available, patients in LMIC are likely to pay more for the medication than patients in the other two groups. Hydromorphone oral solid IR was the most expensive formulation (Me=228.5) followed by oxycodone (IR: Me=144.1; SR: Me=112.6).
      Table 3Morphine Oral Solid, IR 10 mg Tablet—Median Price Per Unit and Median Price Ratio (MPR) by Income Groups
      GNI GroupMedian Price (10 mg), USDMPR
      HIC0.030.06
      UMIC0.100.22
      LMIC0.160.33
      LIC
      GNI=Gross National Income; HIC=high income country; UMIC=upper middle income country; LMIC=lower middle income country; LIC=low income country.
      MPR=difference between the reported dispensed price and the international buyer reference price. The 2011 international buyer reference price for morphine oral solid IR 10 mg tablet was USD 0.47.

      Management Sciences for Health (MSH). International Drug Price Indicator Guide 2011. Available from: http://erc.msh.org/Accessed April 21, 2012.

      Table 4Median Price Comparison of One 30-Day Opioid Treatment By Income Groups
      MedicationAll (n=26)LIC (n=8)LMI (n=6)UMI (n=9)HIC (n=7)
      FreeMe USDFreeMe USDFreeMe USDFreeMe USDFreeMe USD
      Morphine oral solid immediate release (tablet and capsule)6/1418.91/10.01/446.81/330.53/64.6
      Morphine oral solid sustained release (tablet and capsule)7/167.51/10.02/544.62/30.02/77.9
      Morphine oral (liquid)7/130.03/30.01/235.11/2114.12/621.9
      Morphine injectable (ampoule)6/1716.81/31.81/331.73/68.41/564.4
      Fentanyl (transdermal patches)5/142.20/327.64/50.01/62.2
      Oxycodone oral immediate release (tablet and capsule)3/11144.10/2525.40/3200.53/670.9
      Oxycodone oral slow release (tablet and capsule)5/14112.60/2734.82/5334.03/710.5
      Methadone oral solid (tablet and capsule)5/100.50/176.62/40.53/50.0
      Methadone oral (liquid)3/88.90/11.33/716.6
      Hydromorphone oral immediate release (tablet and capsule)0/2228.50/110.50/1446.5
      Hydromorphone oral slow release (tablet and capsule)1/397.71/397.7
      Hydromorphone oral (liquid)
      Hydromorphone injectable (ampoule)0/15.20/15.2
      UMIC=upper middle income country; LIC=low income country; LMIC=lower middle income country; HIC=high income country; Me=median; USD=U.S. Dollars.
      Note: In column “Free” the nominator equals number of countries where medication is dispensed free, denominator equals number of countries where medication is available.

      Affordability

      The mean number of days' wages required by the lowest-paid worker to purchase a 30-day treatment of morphine oral solid IR among the 14 countries that reported availability was five days (Me=0.1; SD=9.1), but varies greatly by country, ranging from: 29.48 (Philippines) and 20.75 (India) to 0.25 days (Spain). In five countries (Nepal, Sudan, Romania, New Zealand, and Poland), it is dispensed free to patients. The results indicate that morphine oral solid IR is less affordable in countries in lower income groups: LMIC (Me=14.4; mean=14.6 [SD=13.1]), UMIC (Me=2.2; mean=2.7 [SD=9.3]), and HIC (Me=0.2 [SD=0.36]; Table 5). In general, a negative correlation between the days' wages and the country income category (Rs=0.544; not significant) was identified: the lower the income, the more working days required to pay for the treatment.
      Table 5Affordability for a 30 Day Treatment of Morphine Oral Solid IR by Income Group
      GNI GroupNumber of Days' WagesCountryNumber of Days' Wages
      All
      • Me=0.1
      • IQR=6.9
      • x¯=5·0
      • CI=4.76
      All countries
      HIC
      • Me=0.0
      • IQR=0.5
      • x¯=0.2
      • CI=0.32
      U.K. (Leeds)0.8
      Spain0.3
      New Zealand0.0
      Poland0.0
      Norway
      Morphine oral solid IR was available in Norway; however, it was not possible to determine the affordability given that there is no minimum wage in the country.
      UMIC
      • Me=2.2
      • IQR=6.0
      • x¯=2.7
      • CI=3.19
      Argentina6.5
      China (Chengdu)4.5
      Romania0.0
      LMIC
      • Me=14.4
      • IQR=25.3
      • x¯=14.6
      • CI=12.84
      Philippines29.5
      India20.8
      Guatemala8.1
      Sudan0.0
      LIC
      • Me=0.0
      • IQR=0.0
      • x¯=0.0
      • CI=0.0
      Nepal0.0
      GNI=Gross National Income; Me=median; IQR=interquartile range; x¯=mean; CI=confidence interval; HIC=high income country; UMIC=upper middle income country; LMIC=lower middle income country; LIC=low income country; IR=immediate release.
      a Morphine oral solid IR was available in Norway; however, it was not possible to determine the affordability given that there is no minimum wage in the country.

      Discussion

      This is the first pilot study that presents information on the differences among availability, prices, and affordability of opioids across the World Bank GNI groups in pharmacies close to a public health facility that provides diagnostic and treatment services for patients with life-threatening conditions such as HIV and cancer.

      Availability

      The information reflects opioid availability in a specific pharmacy on any given day, so no inferences regarding availability in the whole country are possible. Although results indicate that several opioids and formulations were not available at the time of the survey, it does not imply that these opioids are never available in such locations. None of the countries included in the study reported not having any opioids available at any time, which is an indication of progress.
      • Joranson D.E.
      Availability of opioids for cancer pain: recent trends, assessment of system barriers, New World Health Organization guidelines, and the risk of diversion.
      The possibility of finding an opioid at the pharmacy is directly correlated to the country's GNI, which is consistent with opioid consumption reports published by the International Narcotics Control Board. The number of medications available in Guatemala was high compared with countries within the middle and low GNI, which may reflect recent efforts to improve availability to pain treatment in that country. Almost all the African countries registered very limited availability, with either none or one opioid available, with the exception of Sudan, which reported having three medications/formulations available. The participating African countries were LIC (Ethiopia, Kenya, Tanzania, and Uganda) or LMIC (Nigeria and Sudan). Recent efforts have been made to improve opioid availability in several African countries, so future OPW reports should reflect increased availability in these countries as well. As suggested by the WHO,

      World Health Organization, Health Action International. Measuring medicine prices, availability, affordability and price components 2008. Available from: http://www.who.int/medicines/areas/access/OMS_Medicine_prices.pdf. Accessed July 14, 2013.

      the availability of medications can be improved through adequate management and realistic assessment of local supply options and needs.
      While this report was being prepared, the WHO published a new edition of the EML, which includes all the morphine formulations and lists oxycodone and hydromorphone as substitutes for morphine.
      World Health Organization (WHO)
      Model List of Essential Medicines.
      The WHO Model List also includes a new section of medications for pain and other symptoms common in palliative care, which will hopefully result in increased awareness about the importance and relevance of having these medications available to relieve suffering of patients with life-threatening conditions.

      Dispensed Prices

      In regard to its international reference price (USD 0.47), the Me price of morphine oral solid IR (10 mg) is 5.8 times higher in LMIC than in HIC. In the former, the cost of additional burdens and requirements resulting from stringent norms and regulations may be transferred on to the patients, whereas in HIC, the costs tend to be covered through other funds and pooling of resources.
      • Gelders S.
      • Ewen M.
      • Noguchi N.
      • Laing R.
      Price, availability and affordability: An international comparison of chronic diseases medicines.
      Hydromorphone oral IR and oxycodone oral IR and SR were the highest dispensed price medications. However, in Iran and Norway, the dispensed price of oxycodone oral IR was lower than morphine injectable; and in Poland, the dispensed price of oxycodone oral SR was lower than methadone oral liquid. Results also show an unexpected favorable price difference for fentanyl TP: it is dispensed free in five countries (1 HIC and 4 UMIC) and the cheapest opioid in seven, indicating that there could be heavy subsidies in place at all GNI levels. For example, morphine oral solid IR tablet was more expensive than fentanyl TP in China (Chengdu), Germany, Guatemala, India, Iran, Norway, Poland, Spain, the Philippines, and the U.K. It would be useful to find out the reasons why morphine is not included in subsidy programs, even in LMIC. Artificially lowering the dispensing price of the most expensive medications and formulations results in an economic disadvantage for morphine oral solid IR and probably also in less demand for this medication. Morphine oral IR is cheaper than other opioids,
      • De Lima L.
      • Sweeney C.
      • Palmer J.L.
      • Bruera E.
      Potent analgesics are more expensive for patients in developing countries: a comparative study.
      • Mercadante S.
      • Porzio G.
      • Ferrera P.
      • et al.
      Sustained release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management.
      NICE clinical guideline draft for consultation
      Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults.
      so there may be insufficient margin to generate profit incentive for pharmaceutical companies to commercialize it. Although availability of several opioids and formulations is desirable, it is also critical to ensure access to morphine oral solid IR solid, which has been proven to be efficacious and safe for treatment of severe pain.
      • Wiffen Philip J.
      • Wee B.
      • Moore R.A.
      Oral morphine for cancer pain.
      Methadone (in both formulations) was priced lower than several morphine formulations in almost all the countries where available and the most consumed in China, Iran, New Zealand, Tanzania, and the U.K.

      Pain & Policy Studies Group. Opioid Consumption Data 2013. Available from: http://www.painpolicy.wisc.edu/countryprofiles. Accessed July 15, 2103.

      It is important to note that methadone is mostly used in substitution therapy for dependence syndrome, but its use as an analgesic has been increasing in palliative care.
      • Weschules D.J.
      • McMath J.A.
      • Gallagher R.
      • Alt C.J.
      • Knowlton C.H.
      Methadone and the hospice patient: prescribing trends in the home-care setting.
      • Auret K.
      • Roger Goucke C.
      • Ilett K.F.
      • Page-Sharp M.
      • Boyd F.
      • Oh T.E.
      Pharmacokinetics and pharmacodynamics of methadone enantiomers in hospice patients with cancer pain.
      • Sylvester R.K.
      • Schauer C.
      • Thomas J.
      • Steen P.
      • Weisenberger A.
      Evaluation of methadone absorption after topical administration to hospice patients.

      Affordability

      New Zealand had the best affordability (nine medications/formulations available for free). Monthly treatment costs of morphine oral solid IR measured in the number of days' wages of the lowest-paid worker varies greatly (Philippines 29, India 21, and Guatemala 8 days). Many people in these countries earn less than the minimum wages used for this study (USD: 2.18, 4.85, and 8.16 per day respectively)
      • Walker P.W.
      • Palla S.
      • Pei B.L.
      • et al.
      Switching from methadone to a different opioid: what is the equianalgesic dose ratio?.
      and live below the international poverty line of USD 1.25/day,

      Human Development Reports. MPI: population living below $1.25 PPP per day (%) 2013. Available from: http://hdrstats.undp.org/en/indicators/38906. Accessed July 14, 2013.

      indicating that the number of working days needed to pay the cost of treatment may be higher than the results in this study and that pain treatment is accessible to only a few who can afford it.
      Governments and policy makers need to take the necessary steps to ensure that the patients are able to receive the treatment that they need. Prices can be reduced by strategies such as manufacturing the oral morphine in the country, eliminating taxes and tariffs, regulating markup charges, and regularly monitoring the distribution chain. However, these measures are related to wider aspects in the respective country such as the Human Development Index.
      • Gilson A.M.
      • Maurer M.A.
      • LeBaron V.T.
      • Ryan K.M.
      • Cleary J.F.
      Multivariate analysis of countries’ government and health-care system influences on opioid availability for cancer pain relief and palliative care: more than a function of human development.

      Limitations

      Although the OPW follows a methodology similar to the one used by HAI/WHO, the latter does not include controlled medications. Opioids are internationally controlled; thus, the availability and pricing are impacted by additional factors, such as markups resulting from safety and security measures required by the national laws on the manufacturing, importation, distribution, storage, and dispensation. This survey is unable to determine the extent of the impact of these measures on the dispensed price of the medication.
      This study is based on the data collected from external collaborators, and it is not possible to determine how rigidly they followed the instructions.
      This study is a one day cross-sectional survey. Out-of-stock situations occur frequently, especially in LIC and MLIC, so the results on availability might differ in a longitudinal survey. However, the results reflect the situation that patients in need of opioids may face in any given day.
      The study is based on a sample of data of a local pharmacy in the selected countries, which is not representative of the whole country. However, the fact that pharmacies were located to major treating centers may indicate that other pharmacies distant from hospitals may have fewer medications in stock.
      The OPW indicates differences in opioid prices among different locations. With the exception of morphine oral solid IR, it does not take into account the differences in purchasing power among countries. Future studies using purchasing power parity should be carried out to measure how prices may affect access to other opioids.

      Conclusion

      The study indicates that patients in LIC and MIC have less access to opioid medications and highlights the need to continue efforts at improving their availability and affordability. Efforts should be made by governments, health care administrators, and pharmacists to ensure that opioids are available in local pharmacies near to the health care facilities that provide care for life-threatening conditions. Results also show an unexpected favorable price difference for fentanyl TPs over IR morphine, indicating heavy subsidies for fentanyl. Additional studies are needed to identify the reasons why morphine, which is cheaper than other medications, is not included in subsidy programs, even in countries with limited resources. Although availability of several opioids and formulations is desirable, it is also critical to ensure access to morphine, which has been proven to be efficacious and safe for severe pain treatment and has been classified as an essential medicine for the treatment of pain by the WHO. Additional studies are also needed to identify the extent that factors such as restrictive laws and regulations have on the dispensed price of opioid medications.

      Disclosures and Acknowledgments

      This study was partially funded by a seed grant from the U.S. Cancer Pain Relief Committee. The funder did not play any direct role in the study development, data collection, data analysis or interpretation, the writing, or the submission of the manuscript. The authors declare no conflicts of interest.
      Contributors: The following individuals made comments to the project proposal and contributed to Opioid Price Watch:
      International Association for Hospice and Palliative Care (IAHPC) Board members: Eduardo Bruera (U.S.), James Cleary (U.S.), Arthur Lipman (U.S.), and M.R. Rajagopal (India)
      IAHPC webmaster: Danilo Fritzler (Argentina) provided the technical support and guidance in the data collection and reporting processes.
      WHO Department of Essential Medicines and Health Products (Geneva): Willem Scholten, Dele Abegunde, Barbara Milani, and Anne Nguyen.
      External contributors: Rosa Buitrago (Panama) and David Joranson (U.S.)
      Participants: Sofia Bunge (Argentina), Mariam Lubna (Bangladesh), Lilian Hennemann (Brazil), Natalie Rodriguez (Chile), Laura Tupper (Chile), Jinxiang Li (China), Di Xiao (China), Aweke Yilma Dubi (Ethiopia), Heike Reineke-Bracke (Germany), Eva Duarte (Guatemala), Ann Thyle (India), Mamak Tahmasebi (Iran), Mildred Agnes Waka (Kenya), Natalia Carafizi (Moldova), Mina Kumari Ranabhat (Nepal), Brian Ensor (New Zealand), Olaitan Soyannwo (Nigeria), Dagny Faksvåg Haugen (Norway), Jesus Eugenio de Jesus (Philippines), Aleksandra Kotlinska-Lemieszek (Poland), Iwona Zaporowska-Stachowiak (Poland), Daniela Mosoiu (Romania), Olga Usenko (Russia), Nahla Gafer (Sudan), Miriam Giraldez (Spain), Mark Jacobson (Tanzania), Alick Kayange (Tanzania), Michael King'ori (Tanzania), Zirimenya Ludoviko (Uganda), Scott Murray (U.K.), Moira Cookson (U.K.), and Maria Mercedes Bernada (Uruguay).

      Appendix. Sample Data Collection Form

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