Pain Control in Latin America: The Optimized Role of Buprenorphine in the Treatment of Cancer and Noncancer Pain

Pain transcends borders. Latin America (LatAm), with a population of about 639 million, is a diverse geographical region facing public health challenges in helping patients who must deal with different forms of moderate to severe pain. Opioid consumption varies among the LatAm countries but ranges from low to moderate based on international standards [1–10 mg/morphine equivalents (ME) per capita annually]. Formularies in LatAm may offer opioid analgesics, and international guidelines discuss the appropriate use of opioids for various painful conditions, but in LatAm access can limit the use of opioids even when indicated. The appropriate role of opioid analgesics for treating cancer and noncancer pain has fallen under scrutiny as the United States and nations in Western Europe face the public health crisis of widespread opioid use disorder (OUD). At a time when key opinion leaders in North America may be advocating a much more limited role for opioid pain relievers, the nations of LatAm must evaluate and even consider expanding the role of opioids in the care of pain patients. Lessons learned from the United States may help guide their considerations. Of particular interest is the role of strong opioids in the management of pain of moderate to severe intensity.

A variety of analgesic products are available: paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs (NSAIDs), and a range of opioid analgesics such as codeine, morphine, oxycodone, and others. Buprenorphine is a strong opioid analgesic with a unique pharmacology that may offer certain advantages over other opioid analgesics in the treatment of certain pain syndromes. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

For the purposes of this article, Latin America (LatAm) is composed of the many nations in Central America, South America, much of the Caribbean, and Mexico. As such, LatAm is large, populous, and extremely diverse. While recent decades have seen an ongoing migration of the population to urban centers, LatAm retains a large rural population with more limited access to healthcare. There is great racial and ethnic diversity in LatAm. While most LatAm citizens have at least some European ancestry, intermarriage among Europeans, indigenous peoples, and others of African or Asian ancestry has produced a genetically mixed population. Historically, the Spanish who settled in LatAm encouraged conversion to Catholicism (today LatAm is 70% Roman Catholic) and cultural assimilation (nearly all of LatAm speaks Spanish or Portuguese), but discrimination was dissimilar to that which occurred in the U.S.. For example, racial slavery was not widespread in LatAm and miscegenation was legal, in that the Spanish seemed to expect mixed-race marriages. The so-called Columbian Exchange initiated when Christopher Columbus transferred a variety of life forms (including humans) to the New World from the Old World had a pronounced effect on LatAm [1], allowing for genomes in LatAm to be evolutionarily novel in that haplotypes have combined in unprecedented ways [2]. Early genetic research has determined that most LatAm individuals today have paternal connections to Europe and maternal connections to indigenous populations [3]. While much work remains to be done, genetics may explain, for example, why LatAm has a comparatively high prevalence of type II diabetes (risk associated with Native American ancestry) [4].

The healthcare system in LatAm is complex, imperfect, and still evolving. While some form of universal healthcare is available in at least eight LatAm countries [5], healthcare resources in many regions may generally be described as being out of alignment with healthcare demand [6]. Universal healthcare is available in Argentina, Brazil, Chile, Colombia, Costa Rica, Guatemala, Mexico, and Brazil [5], but each nation has its own unique system with peculiarities. Colombia made healthcare a constitutional right for its citizens in 1991 and runs a national insurance program with government subsidies. Mexico has two nationally supported systems: one for retired people and the other for the rest of the population, but private insurance is increasingly popular [7]. Brazil’s system likewise is a hybrid of a taxpayer-funded health system and private insurance products that are used by about 25% of the population to supplement care [7]. However, gaps in the system can be daunting. About 30% of LatAm citizens have no access to healthcare for any number of reasons, including financial restrictions, geographic impediments, and lack of available services [8]. Nevertheless, there appears to be an increased social and political drive to expand and improve health coverage. Some of the challenges facing LatAm healthcare are summarized in Table 1.

Epidemiological data show that LatAm has made and continues to make considerable progress in healthcare [9]. In the last three decades, life expectancy has increased by about 9 years, and is now approximately 65 years for men and 74 years for women [10]. The “graying” of LatAm is one aspect of these extended life expectancies and better healthcare, such as “managed” cancer patients. LatAm has a comparatively high rate of healthcare expenditure associated with injury, with about 20% of all potential years of life lost in LatAm caused by trauma [11]. About 50% of all potential years of life are lost to some form of noncommunicable disease (such as cardiovascular disease, stroke, or cancer) [11]. As is evident in much of the rest of the world, smoking rates in LatAm are declining overall [12]. In LatAm, an inverse relationship has been observed between income and prevalence of tobacco consumption [12]. Obesity remains a public health crisis in LatAm, where body mass indices (BMI) of 30 or more occur in 37.6% of citizens of Uruguay (highest) and 13.3% of Cubans (lowest) [13]. It has been estimated that every 5-point gain in BMI confers on the individual a 30% greater risk of mortality, typically due to vascular disease, diabetes, cancer, kidney dysfunction, liver disease, or respiratory disorders [14]. Thus, the increasing rates of obesity are a major public health concern.

Pain is prevalent in LatAm. This may be exacerbated by obesity, which is associated with pain, particularly joint-related pain [15]. Obesity-associated inflammation may also induce paroxysmal pain via neural damage [16]. In addition, chronic pain tends to increase with advancing age. As the population of LatAm ages, rates of cancer and obesity increase, and the area maintains its relatively high rate of injuries, treating pain safely and effectively will emerge as a growing (and possibly unmet) urgent medical need.

Pain in LatAm is not always effectively treated because of limited access to opioid analgesics, widespread use of less-effective nonopioid pain relievers, regulatory and legal barriers, a lack of clinician training in opioid prescribing, and cultural reservations among patients about the use of such drugs [17]. Concern about the public health crisis in the United States involving opioids may make clinicians, regulators, politicians, and patients uneasy about the use of opioids as pain relievers when there are nonopioid products available.

Optimal pain control requires analgesic therapy to be individualized to meet each patient’s needs; for this, the prescriber must have access to the full armamentarium of pain relievers, including opioids. Medical key opinion leaders in LatAm have recently advocated changes to pain control guidelines that would allow the broader use of opioids in selected cases of chronic noncancer pain [18]. Opioids were advocated for the control of cancer pain by the World Health Organization over a quarter century ago with its now-famous “pain ladder” that called for increasingly strong pharmacological options to address increasingly severe cancer pain intensity levels [19]. About 20–50% of cancer patients experience pain, and 80% of patients with advanced-stage cancer have moderate to severe pain [20, 21]. This pain can occur at multiple sites [22]. Cancer patients experience pain related to the growth of tumors but also pain associated with treatments (chemotherapy-induced peripheral neuropathy [23] and postsurgical pain), and may have unrelated painful conditions as well. Obesity may compound these risks [24].

Large-scale broad epidemiologic studies have not been conducted in LatAm to provide more specific data on pain, its burden to the healthcare system, and opioid use patterns by country or population groups [25]. Opioid consumption is low to moderate in LatAm by international standards, which suggests that much pain is inadequately treated [26]. However, opioids may not be universally available to all indicated patients in LatAm [27]. Where pain is under-treated or ignored, there are usually multiple factors in play, including legal restrictions, regulatory issues, limited access to care, deficits in provider education and training, cultural attitudes, patient prejudices against opioids or pain relief in general, limited or no reimbursement, or other financial restrictions [28]. In some parts of LatAm, opioid analgesics may be considered too expensive for other than very short-term use [27]. It is not known how much the opioid crisis in the United States is shaping the decisions of international prescribers.

Buprenorphine is increasingly being explored by leading medical centers around the world as an important opioid analgesic option, in that it is associated with fewer and less intense psychoactive effects compared to other strong opioids, such as oxycodone [29]. Buprenorphine is not particularly sought by drug-seekers as it has been shown to have low “likeability” [30]. Its withdrawal symptoms are typically less severe than those of other strong opioids [31]. Anecdotally, it is known to the authors that in the U.S., where buprenorphine is a Schedule III controlled substance rather than a Schedule II controlled substance such as oxycodone or morphine, some prescribers prefer buprenorphine to other strong opioids such as oxycodone because it has a lower risk for misuse. In addition, the transdermal formulation of buprenorphine provides convenience and may improve patient adherence [32]. Transdermal buprenorphine may be helpful for patients who require strong analgesics but have difficulty swallowing, have a high pill burden, are involved in complicated treatment protocols that already require taking multiple oral drugs, tend toward noncompliance, or are cognitively impaired or extremely stressed with their treatment protocol.

Buprenorphine possesses a unique pharmacology in that it acts as a partial agonist at the µ-opioid receptors although it provides analgesia as a full agonist; it also acts on the κ-opioid receptors [30, 33]. It is more potent than morphine and has a “ceiling effect” for respiratory depression (meaning that beyond a certain dose, the risk of respiratory depression does not increase), but not for analgesia [34]. In humans, buprenorphine undergoes extensive metabolization, with only a small amount of the parent drug excreted by the kidneys [35, 36]. Most of this metabolism corresponds to N-dealkylation to norbuprenorphine via the cytochrome (CYP)450-3A4/5 enzymes [37, 38]. Buprenorphine and norbuprenorphine are subject to glucuronidation via the UDP-glucuronosyltransferase (UGT) enzymes to buprenorphine-3-glucuronide (B3G) and norbuprenorphine-3-glucuronide (N3G) [39]. Peak plasma concentrations of norbuprenorphine exceed those of buprenorphine [40]. Originally, the metabolism of buprenorphine to norbuprenorphine was considered an inactivation pathway [41], but subsequent research indicated that it may actually be a pathway to bioactivation instead [39]. Glucuronidination is generally considered a form of detoxification and an inactivation pathway. To date, the pharmacological effects of norbuprenorphine glucuronides remain to be elucidated [39]. Norbuprenorphine is a powerful opioid agonist that appears to be more potent than buprenorphine [42]. Norbuprenorphine has affinities for the µ-, δ-, and κ-opioid receptors [43].

The transdermal delivery system for buprenorphine relies on a matrix (patch) to deliver buprenorphine through the skin, avoiding first-pass hepatic metabolism. In many LatAm countries, transdermal buprenorphine is available in low doses (5, 10, and 20 µg/h) that are designed to be applied once every 7 days for prolonged release. The transdermal patch eliminates the issue of patient adherence in that the patient need not remember to take oral medications on a by-the-clock schedule. It is eliminated hepatically (2/3 as norbuprenorphine) and renally (1/3) [33]. Buprenorphine is a potent opioid, but when delivered at low doses it can provide adequate analgesia with adverse effects similar to those of other opioids [44].

The authors were unable to find randomized clinical study data from trials conducted in LatAm, although there are numerous clinical studies on the role of buprenorphine in a variety of painful conditions. The paucity of clinical trials in LatAMm extends beyond buprenorphine and pain management and may reflect an overall low scientific productivity in the region, financial constraints, lack of a clinical infrastructure suitable for running large randomized trials (such as limited numbers of institutional positions), and an expectation that studies be conducted in developed nations [45]. Thus, we present clinical trials from other parts of the world with the expectation that these are relevant to pain patients in LatAm. A review of low-dose transdermal buprenorphine in the treatment of chronic noncancer pain found that the patch (5, 10, or 20 µg/h) was better tolerated than sublingual buprenorphine and provided effective analgesia for patients with osteoarthritis (OA), low back pain, and other forms of chronic nonmalignant pain [46]. Specific study results for transdermal buprenorphine follow.

LatAm is the large, growing, vibrant, diverse home to over 8% of the world’s population. It is likely to emerge in the coming decades as an economic powerhouse. Its tremendous cultural, genetic, and political diversity makes it difficult to discuss as a single geographic region, but there are some important considerations for LatAm as a whole with respect to pain. Pain is a universal condition and pain control has been put forth by respected international bodies as a fundamental human right [70, 71]. Pain should not be ignored, particularly since modern medicine has made available to clinicians a myriad of pain-control products. The current public health crisis of opioid abuse in the United States should not fuel opiophobia in LatAm, but rather help guide LatAm prescribers in how to optimize the role of opioids rather than just avoid them. In fact, LatAm may be in a unique and important position to craft opioid policy and practices that support pain control and minimize risk of OUD by considering lessons learned in the United States in the past decades (see Table 2).

Physicians in LatAm have a unique advantage in that they can help to shape their nations’ pain control policies in ways that confer analgesic benefits to pain patients without undue public health risk. OUD is a serious concern and must not be taken lightly, but pain is also an important consideration. Unrelenting moderate-to-severe pain can destroy lives, tear apart families, derail careers, contribute to disability, and cause financial devastation. Patients facing untreated pain have a decreased quality of life; suicide rates are higher among those with unrelenting pain [72]. The appropriate pain control regimen can improve patient function and boost quality of life.

The role of strong opioids in pain control is important. This article focused on transdermal buprenorphine, as it appears to be an excellent all-round choice of opioid analgesic for both cancer and noncancer pain. It is a strong, effective drug; it can be safely used in those with impaired renal function and geriatric patients (without dose adjustment); it has a ceiling for respiratory depression; it is not a drug that drug-seekers tend to “like” and abuse; and it is available in a transdermal patch system that may confer its own advantages over oral opioids. This is not to say that transdermal buprenorphine should be the only consideration. Pain control regimens should be the result of shared decision-making between prescribers and patients and, in some cases, their families. There are numerous nonpharmacological and pharmacological methods for pain control, and combination therapy is often helpful. Opioid therapy may not be the first-line approach. Opioids may be combined with nonopioids such as NSAIDs for effective pain relief with a net opioid-sparing effect. When it is determined that a patient is indicated for opioids and deemed to be a suitable candidate, opioids should be trialed with a specific “exit plan” in mind, as many patients find opioids ineffective or cannot tolerate opioid-associated side effects. The lowest possible effective dose should be used. For other than short-term use, titration is often required over several days or weeks. Patients may find certain opioids less effective or less tolerable than others; opioid rotation (to another opioid agent) may be helpful in some cases [73]. Opioids may be combined with nonopioid agents for a net opioid-sparing effect.

There is no “one size fits all” solution to pain. Each patient must be reviewed and considered individually and holistically. A very old terminal cancer patient in severe pain at the end of their life is a different case than a younger active patient with moderate occasional knee pain from OA. A patient with a lifelong history of substance abuse and vague pain complaints is a different case than a patient with no such history trying to cope with a few days of postsurgical pain in the hospital setting. Physicians must be advised that, just as each case is unique, each case changes over time. Risk factors for opioid use disorder may be described as dynamic [74]. Physicians and other clinicians should develop relationships of trust with their pain patients, utilize strategies of shared decision-making to find the most appropriate solutions for the pain of each individual, and monitor patients closely to be sure that pain control is effective and its side effects are tolerable. As such, patient education as well as provider training are crucial.

Pain in LatAm may be undertreated, but learning from the U.S. experience with opioids may help guide the diverse nations of LatAm toward a better opioid policy that treats pain effectively without encouraging opioid abuse. There are many reasons that opioids are underutilized in LatAm compared to other parts of the world, including regulations, culture, and accessability. Buprenorphine may be a particularly useful opioid for LatAm patients in that it has a unique pharmacology (ceiling effect for respiratory depression), is appropriate for geriatric as well as younger patients without dosing adjustments, is less well “liked” by drug seekers than other strong opioids, and is available in a transdermal system that may provide enhanced patient convenience and possibly drive better compliance. Pain should not be ignored, and finding better pain control solutions is a global concern.