Physician’s role in prescribing opioids in developing countries

Abstract

In developed countries, addressing the growing opioid addiction epidemic is focused on preventive measures, developing better overdose-reversal medications and designing newer strategies to treat addiction. Primary prescribers of the therapeutic use of opioids might play a definite role in the aetiology of the epidemics. Developing countries could be affected by similar issues; however, given that no updated statistics are available, it is possible that their populations undergo problems similar to those for which current data is available. Concerns have arisen regarding synthetic opioid tramadol which, given its fast and potent analgesic effects, low cost and easy availability is widely prescribed. A debate remains as to whether tramadol induces addictive effects like those of stronger analogues such as oxycodone or fentanyl. Here we present a case of tramadol dependence in an Ecuadorian patient and find that substance abuse can occur in normal individuals affected by chronic pain, otherwise treatable with standard methods.

Case presentation

Our patient is a young man in his 30s living in a rural area on the coast of Ecuador in South America with a medical history of migraine episodes since childhood. This illness was reported on the maternal side of his family for many generations. His disease, as described to a neurologist is spontaneous, with onset at temporal regions, predominantly right-sided, in crescendo in nature and eventually reaching a 10/10 score on the Visual Analogue Scale of pain. It worsens on sleep deprivation and is always accompanied by photophobia, phonophobia and nausea. Migraine episodes were of short duration (about 10–15 min), occurred six to eight times per year and were temporarily solved by different over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs).

As years passed, and without apparent cause, migraine episodes became more frequent, more intense and longer lasting (45–60 min) which left him temporarily unable to perform his daily duties. He did everything possible to control his incapacitating headaches without seeking specialised care to avoid related costs, as he belongs to a low socio-economic class and has heavy financial responsibilities since he has to care for his large family. He has no history of illegal drug use.

In 2018, he suffered a particularly severe migraine attack for which over-the-counter medications were ineffective. So he finally decided to visit a small walk-in healthcare facility where a routine consultation was carried out, along with administration of an intramuscular injection of 100 mg of tramadol. The patient clearly remembers the miraculous effects of the drug and enthusiastically states that ‘receiving such injection was comparable to being in heaven’. For the first time in many years, he felt complete and fast relief from episodic and resilient pain which had accompanied him for almost his entire adult life.

A few weeks later following a new episode, he returned to the very busy medical facility and another intramuscular injection of the ‘immediate cure’ was given after a general practitioner performed a routine medical examination. His visits to such medical units became increasingly frequent and he always received the ‘magical injection’ which gradually became ‘the only medicine on earth capable of alleviating my pain’. Since his strenuous job did not allow him to attend walk-in clinics every time another migraine episode occurred, he managed to obtain written prescriptions from a physician which allowed him to acquire the medicine from any local pharmacy. Later the opioid was acquired from irregular sources which the patient does not want to disclose.

On one occasion, he noticed the inscription ‘for intramuscular or intravenous use’ on the medication label and asked one of the pharmacists if he could use it intravenously for faster onset of action. The professional obviously reassured him that indeed ‘all medications work better when given intravenously’. So the patient requested an intravenous injection and noticed faster onset of relief and a more powerful effect. From then on, the frequency of use escalated and pragmatic need for self-administration arose. During the last few months, the frequency of use reached eight intravenous injections of 100 mg tramadol per day.

During physical examination, we found a pleasant, intelligent, healthy and athletically built individual who was alert and correctly oriented to time and space. Vitals signs were within normal ranges for sex and age, and anthropometry and clinical measures of body composition were also normal. Multiple puncture injuries around superficial veins on both arms were observed. Ophthalmoscopic and eye fundus examinations were unremarkable, and cardiac auscultation and bedside ECG displayed no abnormalities. Thorough neurological examination was normal for both motor and sensory as well as for cognitive and executive functions. The remaining physical examination was within expected limits. His psychiatric examination and results of the Opioid Risk Tool,¹ the Screener and Opioid Assessment for Patients with Pain² and the Screening Instrument for Substance Abuse Potential,³ which were retrospectively administered, showed results within expected ranges and indicated he had a normal risk profile for substance abuse.

Parameters of basic haematology, clinical chemistry and tests for liver and kidney function as well as urine analysis were within normal ranges. A non-contrast brain CT scan found no abnormalities. When asked about tramadol misuse, the patient expressed awareness and admitted to recently having acquired knowledge of its lethal potential. He repeatedly expressed fear since he had already suffered three episodes of generalised seizures during self-administration of high doses of tramadol. Furthermore, he also confided us even his suicidal thoughts when he cited his ‘despair and willingness to end it all’, especially considering his earnings are spent to acquire the opioid with obvious misplacing of his family financial support. Moreover, he repeatedly asked for professional help and stated his desperate need to find something to relieve the pain that has brought him this far. Further, he acknowledged that the use of tramadol calms his recent ‘profound sensation of emptiness and anxiety I have whenever I miss a dose’.

In summary, our patient is a diligent individual who engages in everyday duties to support his family. He is normal from a psychiatric standpoint and has no enhanced clinical risk factors for substance abuse as determined by standardised tools and questionnaires.^1–6 Considering these precedents, especially his normal risk profile, he seemed unlikely to become addicted and was just another subject who needed effective means to relieve his pain. When the first general physician who evaluated him prescribed tramadol and it attained seemingly miraculous results, it seemed that a long-standing problem had been solved and that the patient’s life had been considerably improved. Unfortunately, the lack of information about the addictive potential of tramadol and the inefficient enforcement of existing regulations allowed him to acquire and use the potent opioid-like substance he became dependent on.

Global health problem list

• Global opioid crisis.

• Physician’s role in prescribing opioids when enforcement of regulations is loose

• Addiction potential of the synthetic opioid tramadol

Global health problem analysis

General issues raised by this clinical case

Despite recent evidence that opioids are poorly effective in treating migraine attacks,⁷ we observed that tramadol worked efficiently in our patient and alleviated his pain. There might be other factors explaining this outcome including those regarding pharmacogenomics and inherent mechanisms related to the properties of drug action on specific individuals.^8–10 Indeed, the M1 O-demethylation metabolite of tramadol has a wide range of 200-fold to 300-fold higher affinity for mu receptors than the original molecule and the significance of its levels in discrete individuals has not yet been determined.^{11 12} Moreover, it is known that individual cytochrome 450 genetic characteristics, especially those of CYP2D6, definitely influence analgesic potency. In addition, ultrafast metabolisers experience faster and greater opioid analgesia along with higher addictive potential,¹³ hence making it probable that our patient belongs to this latter group. Although we could not perform specific studies regarding genetic predisposition or drug metabolism characteristics in this subject submit the possibility of background predisposing factors explaining the peculiarities surrounding his response.

It should be noted that the importance of CYP metabolism of opioids has led to development of pharmacogenomics-based computer-assisted decision-making systems in major medical centres. These tools provide physicians with objective and practical means for correctly approaching a life-determinant event in the treatment of chronic pain.¹⁴ This clinical case study also underscores the need for implementing these strategies in medical centres in economically less developed countries. Integrated and sophisticated approaches of this nature could have disclosed inherent influences occurring in our patient but, responsibility for his opioid misuse appears independent of intrinsic factors and burden seems to rest on a combination of elements derived from an inefficient health system. Indeed, general physicians that must work in medical units overloaded with patients have very limited time for individual consultations. Moreover, they have to deliver their practice within a system that not only needs more physicians per unit but also a stricter supervision by health authorities, which includes measures regarding the refill of opioids and opioid-like drugs in pharmacies.¹⁵

In a different but related aspect it should be noted that once a health problem with dire consequences for the population appears and establishes itself, definite conclusions on its origin and characteristics are usually drawn from large epidemiological studies. Nonetheless, a closer look at individual patients could give leads to understand or even disclose unique underlying features shared by most subjects affected with the condition, and while shedding light on certain peculiarities of the epidemic it also provides the basis for a better design of comprehensive and more integral solutions. In this context, the patient-physician relationship which is the most important aspect of medical practice is the one that might lead to the identification of general determinants underlying the new health issue in the population in affected individuals. 

In this report, we describe the case of a patient who goes to a physician requesting help to calm his pain and obtains effective and rapid relief. Nevertheless, because of inherent inefficiencies such as excessive number of patients seeking care in small units, weak supervision by health authorities and opioid availability from irregular sources, a very complex health issue ensues: addiction to pain killers of opioid essence. In accordance with previous statements, we felt it necessary to directly quote our patient to illustrate that individuals enduring pain and its consequences can identify in simple terms, essential determinants of a larger health problem because they are feeling in themselves most of its consequences. 

The search for analgesic medications to alleviate pain is one of the main and most ancient objectives of a physician’s profession and to this end natural opioids have been used for centuries to mitigate human suffering.¹⁶ Analgesia induced by opioids is mediated by their binding to the mu receptors regulating pain perception in brain regions such as periaqueductal grey matter, thalamus, cingulate cortex and insula.¹⁷ In addition, neuronal projections to amygdala and neurons of mesolimbic pathways also express these types of binding sites thereby allowing opioid medications to exert effective analgesia, along with a generalised perception of pleasure and euphoria.¹⁷ It is this combination of pain relief and pleasant sensations that make chronic pain users of these drugs prone to addiction.

In the late 1990s, the medical community was somehow convinced that patients with chronic pain would very seldom become addicted to synthetic opioids and healthcare providers prescribed them more frequently,¹⁸ which led to widespread use and misuse. Much later, it became clearer that these medications could be highly addictive.¹⁹ Nevertheless, during the period of unrestricted opioid prescription, misuse increased dramatically and became a major contributor to the crisis that nowadays is a major public health concern for authorities in developed countries and that is affecting North Americans in particular, as referenced by statistics.

Current approaches to deal with the opioid epidemic focus on newer strategies to manage chronic pain^{20 21}; however, the role of the physician as a primary barrier to possible addiction remains underestimated, poorly discussed and most of the times, simply ignored. In Ecuador, which is an economically less developed country, there are no statistics about the use and misuse of prescription opioids, and it is not known if its population is affected by issues comparable to those of the USA. In our setting, one easily available and widely used opioid-like medication is tramadol. As previously stated, it remains controversial if this drug induces addictive effects similar to those of stronger opioid analogues such as oxycodone, morphine or fentanyl¹¹; however, the clinical case presented here illustrates that it is a distinct possibility that must be considered by prescribing physicians.

The global problem

In 2016, more than 42 000 Americans died because of opioid, heroin and fentanyl abuse which is an average of 115 people dying every day from an overdose of opioids.²² Among fatalities, more than 40% stemmed from opioids prescribed for chronic pain which is the highest percentage ever documented by the Centers for Disease Control and Prevention (CDC).²² When observing the 2015 and 2016 statistics, it can be seen that despite all efforts and plans implemented by public health authorities, improper opioid use rates were not significantly reduced, especially in the population above 25 years of age.^{23 24}

In addition, an estimated 4%–6% of patients that misused prescription opioids transitioned to heroin,^{25 26} and history of irregular use of prescription opioids was found in about 80% of people who are currently heroin addicts.²⁷ Suspected opioid overdose events at emergency units from July 2016 through September 2017 demonstrated an increase in the prevalence determined in 52 areas of 45 states of the USA, being highest in the Midwest (69.7%), followed by West (40.3%), Northeast (21.3%), Southwest (20.2%) and Southeast (14.0%).²⁸ The CDC estimates the economic burden of prescription opioid misuse in the USA to be US$78.5 billion per year including costs for healthcare, lost productivity, addiction treatments and crime derived expenses.²⁹

Tramadol, an opioid-like substance, is a central acting synthetic analgesic which acts both, as a weak mu-opioid receptor agonist and as a serotonin/norepinephrine reuptake inhibitor.³⁰ Despite extensive preclinical, clinical, postmarketing surveillance results and epidemiologic data suggesting relatively low abuse/dependence potential, and risks estimated to be comparable to NSAIDs,³¹ deep concerns regarding its addictive potential and proper regulatory classification have arisen.

Information regarding the pathophysiological events underlying opioid and tramadol addiction can be found in recent literature^32–34; yet, it is worth mentioning that several intrinsic predisposing factors have been established for individuals at high risk for dependence, especially for those with tendencies to overdose.³⁵ In consequence, history of addiction to any substance (alcohol, benzodiazepines or opioids),³⁶ kidney or hepatic dysfunction, diminished drug clearance patterns,³⁷ as well as history of suicidal thoughts or attempts must be taken into account before prescribing opioids and opioid analogues to predisposed subjects. It should also be noted that health problems associated with respiratory depression, or administration of agents with respiratory depressant effects (eg, benzodiazepines, sedative hypnotics) have been associated with lethal events.³⁸ In any case, clinical assessment of these risk factors can be done with validated questionnaires and similar tools.^1–6 We adhere to suggestions that their use should be further encouraged.

The responsibility for the opioid crisis resides with governments, health authorities, pharmaceutical companies, pharmacies, physicians, healthcare providers and lastly with addicted people. Comprehensive solutions need input from those mentioned and involved. However, while waiting for structural mid-term and long-term solutions and prevention policies, it should be emphasised that the immediate duty to act and control specific prescriptions remains with practicing physicians, especially considering their immediate and direct contact with affected subjects who are being attended  at this very moment.

When evaluating the factors related to the onset of opioid misuse in this study case, we acknowledged that the medical prescriptions indeed controlled the legal use of tramadol in the acute and chronic circumstance and played an unintended role in the aetiology of the misuse of a medication which was otherwise given with the intention to heal. It is worth noticing that these events also happened because of misconceptions about the addictive potential of synthetic opioids so it should be stressed that before prescribing tramadol, or any other similar medication, we physicians must approach pain management in the stepwise model established on the guidelines of the WHO and similar entities.^39–41 In addition, complete medical history, thorough physical exam and accurate differential diagnosis of specific pain conditions must be done to attain a proper risk-benefit solution, especially when treating chronic conditions that may be disguised as single isolated events. Unfortunately, heavy patient load in most clinical units has determined that fatigued physicians are forced to reach for immediate and effective solutions, without having the necessary time  to fully evaluate the profound implications that a decision of this nature entails.

Most industrialised countries enjoy technological advances which have positively influenced social conditions and access to medical attention, hence inducing an augmented life span and resulting in an increased number of ageing individuals who eventually will be affected by chronic pain. Combined results of these variables will ineluctably create further pressure in already inefficient medical systems, elevate physician’s work-time and diminish the time required for proper individual consultations. Moreover, since a direct relationship exists between higher physician’s workload and quality of medical attention, unavoidable deterioration of care should be expected. In fact, when workload and autonomy were assessed as determinants of physician burnout in 890 physicians from six different specialties, workload correctly predicted higher levels of physician’s burnout and physical fatigue.⁴² Burnout is associated with less humane approaches, lowers patient’s involvement in decisions and further limits physician’s care time, eventually resulting in decreased diagnostic accuracy, misdiagnosis, rushed decisions, increased iatrogenic outcomes and generalised poor quality of care.⁴²

In Ecuador, a still developing country, measures aimed to widen the medical coverage of the population are being undertaken by health authorities and newer public policies are oriented to attain this aim. However, an insufficient number of available physicians for a higher number of patients generates overburdened medical units, lesser consultation time and physician burnout eventually resulting in diminished quality of medical attention.

In any case, once the decision to use opioids and opioid-like substances is made, warnings about their addictive potential should be routinely provided to every patient. Besides the obvious, these should include information on hazards involved in sharing prescriptions, advice on the importance of preventing others from having access to personal medications and recommendations for secure storage of these potent drugs. Also relevant, assessment of individual risk factors for substance abuse via standardised questionnaires^1–6 should be performed, especially before granting refill prescriptions. Implementing each of these time-consuming but necessary measures implies vast changes in present medical systems but, nevertheless, it is indispensable to control and monitor the present as well as to prevent future epidemics of therapeutic opioid misuse.

Learning points.

• In more economically developed countries, epidemic opioid misuse stems from intrinsic and extrinsic factors. Similar issues must also exist in economically less developed countries.

• Given our function as immediate controllers of prescription, we physicians play a cardinal role in the genesis of misuse of therapeutic opioid pain-killers.

• Physicians controlling the initial access of patients to therapeutic opioids, while serving individuals who need professional help to efficiently and safely alleviate their pain, must always consider the addictive potential that synthetic opioids inherently have.

• Synthetic opioids such as tramadol can induce dependence even in subjects showing normality in the standard clinical evaluation of addiction risks.