The Introduction and Experiences of Methadone for Treatment of Cancer Pain at a Low-resource Governmental Cancer Center in India.

OBJECTIVES: This study aimed to describe the clinical experience of the health-care professionals (HCPs) responsible for the introduction of methadone, for the treatment of complex cancer pain, at a low-resource hospital in India in a patient-group, burdened by illiteracy, and low socio-economic status.
MATERIALS AND METHODS: Ten HCPs: Four medical doctors, four nurses, one pharmacist, and one hospital administrator were interviewed. The interviews are examined using a qualitative conventional content analysis.
RESULTS: The interviews showed a confidence amongst the HCPs, responsible for the safe introduction of methadone in a stressful and low-resource surrounding, to patients with cancer pain and the different aspects of methadone, as initiation, titration, and maintenance of treatment.
CONCLUSION: Introduction of methadone for cancer pain management is safe and feasible although low resources in a challenging hospital setting and care environment.

INTRODUCTION

Treatment of pain is paramount in the care of cancer patients, whether the pain is caused by the disease itself or by procedures and therapies involved in the care. Pain control is crucial for the patient’s quality of life (QOL) and for the patient’s confidence toward health-care professionals (HCP) involved in the care and is thus of critical importance for the compliance to medical care.[ However, to accomplish an individualized pain-treatment several prerequisites needs to be met. First and foremost a good awareness and understanding of the importance of pain-assessment, a knowledge of the indications and contraindications, the pros and cons of different pharmacological treatments and in addition to this also the non-pharmacological treatment options that are feasible and available.[ Moreover, the access to internationally recommended drugs is absolutely fundamental and indispensable, that is, that these drugs are available and affordable and of no difficulties for the patients to access.[

The World Health Organization (WHO) has listed opioids as essential medicines, that is, medicines for worldwide priority healthcare needs. However, the access to opioids is very unevenly distributed globally with vast and unacceptable disparities between developed and developing countries.[ Treatment of pain can on a global level roughly be compared by the legitimate medical use of opioid-based analgesics. It was estimated, in 2010, regarding legal global opioid consumption in the treatment of pain that four High Income Countries accounted for 68% of the worldwide consumption, while all Lower-Middle Income Countries (LMIC) together only accounted for 7% of the global use.[ Furthermore, it is estimated that 83% of the worlds’ population is left without effective pain treatment.[ This is despite improved knowledge in the field and actions taken by different organizations, among them the WHO, to relieve the global burden of cancer pain.[

In 2012, the European Society for Medical Oncology’s Palliative Care Working Group and Developing Countries Task Force presented an overview of conceivable barriers which may limits the access to opioids and treatment of cancer pain. In India, The Indian Association of Palliative Care and many other civil societies, non-governmental organizations and individuals launched a successful advocacy campaign to improve access to opioid medications for medical use. The Supreme Court of India then issued claims to all Indian States to ensure availability and ease of access to opioids for adequate cancer pain management end-of life. In the year 2014, the Government of India amended the old Narcotic drugs and Psychotropic Substance Act with an intention to simplify the regulation around procurement of opioids medications under the category “Essential Narcotic Drugs” but today opioids are still not provided in a large number of Indian states.[

In India, opioid-treatment is still hampered by misconceptions, doubtlessly due to the lack of proper training and knowledge in pain management amongst HCP.[ The global needs of opioids, for the treatment of cancer pain, can be met as morphine is inexpensive to produce and largely not protected by patent restrictions.[

Methadone - an opioid for the treatment of neuropathic pain

Methadone is often used as an adjuvant analgesic (as an add-on), to an existing opioid (mainly morphine) treatment.[ Methadone as replacement for morphine, as a primary opioid, is frequently used in patients with persisting pain despite high doses of regular opioids, and when opioid tolerance during treatment with morphine occurs.[ It is also applied in patients suffering from non-acceptable side effects from regular opioids, as hyperalgesia, or in patients with kidney-failure.[

Methadone is an opioid that was initially developed in the 1940s, as an alternative to morphine. It has been widely used to treat heroin-addiction but has in the recent decade received more attention as an analgesic for neuropathic cancer pain.[ Methadone in pain-treatment is afflicted by distrust.[

Methadone’s pharmacokinetic (PK) and pharmacodynamic (PD) features are characterized by its affinity to the mu receptor and an antagonistic effect to the N-methyl-Daspartate (NMDA)-receptor. The NMDA-receptors located in the dorsal horn of the spinal cord are the main targets for pharmacological treatment of neuropathic pain.[ The challenge with methadone is it’s long half-life with individual variations of 8.5–47 h,[ a tissue accumulation and interactions with many other drugs that also, as methadone, are metabolized in the liver by cytochrome P450.[ Methadone has been showed, in the adult population, to have cardiac side effects and to cause a dose-dependent effect on the QT-interval, which in rare cases could result in a drug-induced Torsades de Pointes (diTdP).[

Other side effects of methadone are to a great extent similar to those of morphine, including nausea, constipation and drowsiness.[

Prescription of methadone is legal in India since 2014, for pain management, but only in use in a few centers,[ whereof the present study hospital is one, since Sep 2017.[

A proper understanding of methadone’s potential as an analgesic and the side-effects is essential for the safe introduction, in India as well as in all LMIC worldwide.[

Aim

The aim with this report was to share the experience, from different perspectives, from different HCP, in introducing a highly potent and efficient and affordable drug for treatment of cancer pain in a low-resource setting.

We hope this report can serve as an encouragement for similar care facilities to consider the use of methadone in the treatment of cancer pain, especially when elements of neuropathic pain are present.

MATERIALS AND METHODS

A semi-structured interview technique was applied with the purpose to review the experiences from the HCP of methadone treatment for cancer pain, both in pediatric and in adult patients. Interviews took place at the hospital with the main researcher conducting all the interviews. Data were collected from the content of the interviews and analyzed using qualitative conventional content analysis, that is, a thematic analysis approach.

Study hospital

Mehdi Nawaz Jung Institute of Oncology and Regional Cancer Centre (MNJ), is a governmental cancer-hospital in Hyderabad, Telangana, with a catchment area of approximately 35 million inhabitants. The hospital provides cancer treatment to approximately 10,000 new cancer patients on a yearly basis with care, free-of-charge for patients below the poverty line. The MNJ hospital is one of few cancer-centers in India with permission to prescribe methadone with a license since 2017.[

Study participants

Eligible HCP were selected by purposive sampling based on their involvement and experiences of methadone in cancer pain at the study hospital. Different professionals were selected to ensure a broad perspective of the responsibilities and viewpoints of methadone-usage. In total ten HCP were eligible and approached, of which two of these (GP, SR) also are co-authors to the article but not involved in the design of the interviews or the coding of the results. Interviews were conducted between November 27, and December 3, 2019.

Data collection

Interviews were created based on topics perceived as important issues, covering HCP perceptions on safety and logistic aspects concerning methadone in the treatment of cancer pain and formulated by CA, EB, MS, and MGM. Specific topics included were; regulations in procurement and prescribing methadone, when to consider methadone treatment, comorbidities and contraindication to assess before initiating methadone, base-line investigations (lab testing and ElectroCardioGram) before initiation of methadone, protocol for initiation and dose escalating of methadone, opioid-rotation to methadone, monitoring of side effects, amount of methadone prescribed each time and iterations, concerns about addiction, instructions about methadone to patients and caregivers, and positive and negative experiences of methadone compared to morphine (full topic list, see appendix). The main researcher, CA, conducted all of the interviews in English. All interviews were audiotaped and transcribed verbatim by CA (for interviews, see appendix).

Data analysis

We reviewed the transcribed interviews by adopting a conventional content analysis method.[ The analytic steps we used, as described by Hsieh and Shannon: First a thorough reading of the text and then subdividing it into content-areas for every interview questions separately. We then extracted and condensed significant meaning units and made abstractions and code-labeling. We sorted the codes into categories and created sub-themes. Finally, we decided on themes, by grouping codes around larger meaning-units whose content reflected the meaningful data in the interviews. The data were coded by MS. A member checking of the data and conclusions, to increase the credibility of the study, was done by all authors.

Ethics approval and consent to participate

Ethics approval by the ethical board of MNJ was obtained before initiation of the study, as part of a larger retrospective review of patients receiving methadone in the treatment for cancer pain, since MNJ was granted license in 2017. Permission for this study was also applied for and obtained from the head of the department of Department of Pain and Palliative Care at MNJ hospital. Informed consent to participate and permission for the audio recording of discussions was obtained from each participant before the interview.

RESULTS

The included HCP, four medical doctors, four nurses, one pharmacist, and one hospital administrator were interviewed. An interpreter participated during the interviews of three of the four nurses and the pharmacist.

Data-analyses of the collected interview-results, from all the participating HCP led to the finding of 34 primary codes, 15 sub-themes, and seven main themes. [Table 1] displays the main themes, sub-themes, and primary codes.

Table 1:

Formulation of themes.

Themes	Subthemes	Codes
The requirement to procure and dispense methadone
	Recognized Medical Practitioner (RMP)	Any medical doctor can prescribe opioids
		Doctors in India are not trained in using morphine or similar opioids
		Trainee is needed
		Training in pain and palliative care
		Special training in using methadone is encouraged
	Recognized Medical Institution (RMI)- status	The license to procure methadone was released by government of India 2014
		Any government hospital can apply for a license to procure methadone
		Drug control authority and certificate
		Annual counter of methadone, what formula is needed.
Procurement of methadone
	Hospital purchasing departement	Committee consisting of four people
		Quotations
		Pharmaceutical companies
Special concerns when prescribing methadone
	comorbidities	Older patients
		Drug-interactions
	contraindication	QT prolongations. Liver cirrhosis
	side-effects	Drowsiness. Confusion.
When to consider methadone treatment
	Neuropathic pain	Unresolved pain on morphine
		Complex neuropathic pain syndrome
	Side-effects to morphine	Morphine induced tolerance
		Hyperalgesia
		Drowsiness. Confusion.
		Renal failure
Base-line investigations before prescribing methadone
	Lab-testing	Electrolytes
	ECG	QT-prolongation
Methadone doses
	Initiation	First-line opioid
		Add-on opioid
	Escalation	Go slow
	Opioid-rotation	Three-day slow-conversion method
Prescription of methadone
	Safety	Instructions to patients and caregivers
		Storages of methadone
		Addiction
	Dispenses of methadone	Formulation of methadone
		Amount of methadone
		Refills of methadone

According to the seven main themes we have, to facilitate for the reader, interpret, and summarized the contents and findings from the interviews (text data).

The requirement to procure and dispense methadone

In India, the prescription of methadone was legalized 2014. Today, any hospital can apply for a license to procure methadone but up until now only a few centers have a license, whereof at the study hospital since September 2017. A hospital has to go through a license process to achieve a Recognized Medical Institution (RMI) – status, which entails several steps to ensure a safe use of methadone. A hospital is required to have sufficient facilities to see patients, a facility to safely store methadone and trained Recognized Medical Practitioners, for the usage of and prescription of opioids. The Drug Control Authority (DCA) then issues a certificate of RMI. The hospital then makes a request to DCA for an estimated annual requirement of methadone prescription.

Procurement of methadone

The DCA issues the hospital, according to the annual requirement of methadone, to procure and purchase the needed amount and desired medical formulation. The Hospital Purchase Section, or as per the hospital protocol, then approaches pharmaceutical companies, with a license to manufacture methadone, and calls for quotations. A hospital committee, consisting of the head of the department, head of the hospital, administrator officer and the resident medical officer, reviews the quotations, and the different tenders and then decides which pharmaceutical company that has quoted the best price and thus which company to approach.

Special concerns when prescribing methadone

A patient history of arrhythmias, due to QT-prolongation, or an end-stage liver cirrhosis are considered as contraindications and such patients will not be considered for methadone treatment. The side effects of methadone are similar to those seen with other opioids. Drowsiness and confusion are the most frequent side effects experienced with methadone.

When to consider methadone treatment

Methadone could be considered in multiple different situations; in a more complex pain situation with unresolved pain despite treatment with regular opioids, in situations with uncontrolled side effects of morphine or of any other regular opioids, as well as in patient with renal failure. Furthermore, an opioid-rotation, to methadone, is an option when morphine induced tolerance is a clinical issue with or without opioid-induced hyperalgesia.

Baseline investigations before prescribing methadone

The extent of baseline investigations depends on where the patient is in the trajectory of the disease. That is, if the patient is receiving treatment with a curative or palliative intent, or if the patient is in a situation close to end-of-life care. In a situation with an ongoing curatively intended treatment, especially in patients receiving chemotherapy, where nausea and vomiting is frequent, electrolyte balance is an issue that must be monitored. Similarly, in patients with comorbidities and multiple medications, drug-interactions and QTprolongation could be a valid concern.[ In a palliative stage of a disease, in end-of-life care, the focus of care is QOL and comfort. Medical investigations that expose patients for painful and/or futile procedures must then be scrutinized.

Methadone doses

Methadone could be used as an adjuvant opioid, in low doses of 2–2.5 mg once or twice daily, to a regular opioid, as morphine. This is especially successful when a neuropathic pain component is suspected and in a situation with an increased risk of side-effect following a dose escalation of morphine.

Methadone could also serve as a first-line opioid, and thus as a primary opioid. When initiating methadone to opioid naïve patients, in a safe way, the “start low and go slow” method, with doses escalations of 2–2.5 mg once or twice daily, with a 5 days interval is recommended.

When preforming an opioid-rotation, from a regular opioid as morphine to methadone, a 3-day slow-conversion method could be employed. The first step is then to calculate the mean equivalent dose of morphine (MEDD), that is, the existing dose of morphine during 24 h, then to use a morphine-methadone conversion ratio chart to identify the equal dose of methadone. To overcome cross-tolerance the methadone dose then must be reduced by 50%. The remaining 50% will preferably be added in a period of 3 days, the 1st day one third of the dose is added, the 2nd day a dose escalation to two thirds, and the past day the full dose is added. Simultaneously, morphine is reduced by one third, two thirds, and then completely withdrawn the 3rd day.

Prescription of methadone

Instructions to patients and caregivers about methadone usage, potential side-effects and how methadone is safely stored in their home, is important. There is however no need for greater concerns of addiction to methadone compared to that of regular opioids. A responsible prescription of any opioid is warranted. Dose-titration must be monitored in close contact with the patient or with the caregiver. Daily follow-ups are recommended for in-patients at the hospital or hospice and by daily telephone calls to patients in a home-care setting, to assess the treatment-response and side-effects during the 1st week. If the patient responds well to methadone, the sum of 1–2 weeks of methadone consumption, either with pills or with syrup, is prescribed from the hospital. If the patient resides far away from the hospital a prescription for up to 1 month is dispensed. The methadone formula (pill or syrup) is decided on the patients’ convenience. The pill is the easiest and safest way to prescribe methadone, with a reduced risk of misunderstanding or miscalculation, compared with the equipotent dose of the syrup formula. On the other hand, in patients with dysphagia and in pediatric patients or when the patient is prescribed very small amounts of methadone the syrup is preferable prescribed.

DISCUSSION

We can report on methadone being introduced, in a stressful and low-resource surrounding to patients with cancer pain, in a safe manner and with confidence amongst the involved HCP covering the different aspects of methadone initiation, titration and maintenance of treatment.

Methadone is an effective analgesic for the management of chronic complex pain such as neuropathic pain seen in cancer and when the pain does not respond or subsides on regular opioid such as morphine or fentanyl. Methadone could also be a useful alternative in clinical situations with opioid tolerance defined as a decreased analgesic effect of regular opioids after repeated and prolonged use.[ Furthermore, methadone is an affordable option to other long-acting regular opioids, less expensive, and more accessible, which is of special interest in LMIC.[ In fact, the MEDD of Morphine (60 mg) and Methadone (10 mg) is equivalent in cost, 7 Indian Rupee (INR) for Morphine versus 6.75 INR for Methadone, in India (Dr Gayatri Palat, personal communication, June 15, 2020).

Methadone is afflicted with misbelief and with an underserved bad reputation of being unpredictable and difficult to monitor.[ and thus with great risk of severe side effects such as diTdP.[ True, the distinct PK and PD properties of methadone require caution when a patient is initiated, titrated, and maintained on methadone. The required dose of methadone, to obtain an analgesic effect, varies from one patient to another due to inter-individual variations but also if any drug-interaction occurs interfering with the PK and the PD. However, in a recent study by Lovell et al. from 2019 a clinically significant difference between the incidences of QT-prolongation was seen between patients treated with low-dose methadone (mean daily dose of 14.3 mg) and patients treated with high-dose methadone (mean daily dose of 86 mg) with an increased risk following the high doses.[ Patients with baseline QT-prolongation had a higher risk of developing QT-prolongation after 2 weeks of treatment compared to patients without a baseline QT-prolongation.[ Clinical studies of low-dose methadone in the treatment of cancer pain in pediatric patients have not showed any significant increase of the QT-interval.[

A low to moderate dose of methadone, as first-line and primary opioid or as an adjuvant opioid, could therefore be considered as a safe treatment of complex cancer pain.

That being said, it is essential that HPC (physicians) prescribing methadone undergo trainee program, in pain management and palliative care with a special focus on methadone, to obtain a good understanding of its usage and the importance of adherence to recommendations, to avoid any serious adverse events. Dose-titration must be monitored in close contact with the patient or with the caregiver. In addition, HCP must ensure that patients and caregivers are provided with clear and easily understood instructions about methadone use, potential side effects, and how methadone is safely stored in their home.

Limitations

Content analysis always involves some level of subjective interpretation. Due to the limited number of participants (ten HCP) and the heterogeneity in their professional role and thus in experiences, findings must be read with some caution. Qualitative approaches have limited generalizability outside the scope of participants’ lived experiences and other clinical settings. The transcribed verbatim interviews’ are attached in an appendix for full transparency.

CONCLUSION

Methadone, in low doses, as the primary opioid, in treatment for complex cancer pain, in a low resource setting, can be safely introduced. Involved HCP, from different categories were confident. Proper training of staff in pain management, clear guidelines on opioid-treatment, and patient - and caregiver education is essential.