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Opioids for the treatment of non-cancer pain
Opioids for the treatment of non-cancer pain
* Professor of Anesthesiology and Medicine. Vice-Chair for Clinical Affairs. Department of Anesthesiology, University at Buffalo. Chief, Pain Medicine and Professor of Oncology. Roswell Park Cancer Institute.
gested by the WHO step ladder, portending that it may not be appropriate to treat every patient in the same way. Thus, the The analgesic ladder was introduced under the auspices of role and the place of opioid therapy in chronic non-cancer pain the World Health Organization (WHO) in 1990(1) with the are better defi ned in the 21st century. Likewise the potential idea of providing health care providers around the world with complications associated with long-term opioid therapy are a tool to help them implement pain therapy in patients with cancer related pain. With the suggestion that opioids could To facilitate the presentation of the arguments, the discus- also be used for the treatment of non-cancer related pain(2), sion will be divided accordingly in distinct clinical conditions the principles of the analgesic ladder were eventually imple- where most of the literature has become relevant to support mented in patients with non-cancer pain(3). Moreover, recent studies have addressed the potential problems associated with the use of non-steroidal anti-infl ammatories (NSAIDs) and PATIENTS WITH OSTEOARTHRITIS (OA)
cyclo-oxygenase-2 (COX-2) inhibitors in the geriatric popu-lation, expanding the indications for opioids in the treatment The fi rst line agent for the treatment of pain associated with of non-cancer pain. The objective of this review is to discuss osteoarthritis is acetaminophen(13). However, as the disease the fi ndings of recent articles published in the literature sug- progresses, patients will eventually not respond to this form gesting that the implementation of opioid therapy in patients of therapy and will need a stronger analgesic for the control with specifi c co-morbidities and drug-drug interactions may of pain. According to the analgesic ladder, the choice would be indicated to avoid signifi cant complications and adverse be a non-steroidal anti-infl ammatory (NSAID), or a cyclo-drug reactions. In fact, adverse drug reactions have been re- oxygenase (COX-2) inhibitor. Well established contraindica- cently linked to polypharmacy(4) and are estimated to incur tions to the use these drugs are renal failure(14) and a history costs in excess of one billion US Dollars annually just in or current evidence of peptic disease(15). There is a wide the United States(5). Since 28% of adverse drug events are understanding among clinicians of this fact. The incidence of preventable and occur most commonly with cardiovascular renal dysfunction is the highest in patients 65 years or older; drugs, diuretics, opioid analgesics, antidiabetic agents and it is dose-related to NSAIDs and COXIBs; ibuprofen, indo-anticoagulants(6), there is also a negative economic impact of methacin, piroxicam are likely to be worse when compared to using inappropriate medications in some patients.
other NSAIDs; pre-existing evidence of renal disease or gout In parallel with these fi ndings, the availability of new increases the odds ratio of renal failure to 6; and the combina- modes of delivery, such as topical analgesics(7), the develop- tion of pre-existing renal disease and gout increase the odds
ment of clinical guidelines for the management of special ratio of renal failure to 82(14). Consequently, the use of these conditions, such as neuropathic pain(8-10), and the develop- agents in the presence of renal dysfunction is ill advised.
ment, and the subsequent critical evaluation of interventional Patients with PUD receiving NSAIDs will have an inci- techniques for the management of pain such as neuromodula- dence of upper gastrointestinal (UGI) ulcer complications tion(11,12), etc., have signifi cantly change the approach sug- 2.9 times greater than those receiving celecoxib, and 2 times Este artículo puede ser consultado en versión completa en
Volumen 35, Suplemento 1, abril-junio 2012 de Leon-Casasola OA. Opioids for the treatment of non-cancer pain greater incidence of complications and symptomatic ulcers signifi cant lower incidence of complications and symptomatic than those treated with the same COX-2 inhibitor(15). More- ulcers (4.7 versus 6%, p = 0.49) than those treated with non- over, risk factors for the development of ulcer complications specifi c NSAIDs(9). In the case of lumiracoxib(21), there were also differences in the cumulative one year incidence of peptic ulcer complications between patients receiving lumiracoxib • History of perforation, ulcer, or bleeding only or non-specifi c NSAID (naproxen or ibuprofen) (0.20 versus 0.92%) and those who received lumirocoxib + ASA or non-specifi c NSAID (0.69 versus 0.88%). The clinical impli- cations of these fi ndings are important as the OA population tends to be 65 years or older, and as a result of that will be frequently receiving mini dose ASA for cardiovascular pro-phylaxis. Thus, one has the option to switch them from ASA to In contrast, it is not as widely recognized that the inci- clopidrogel or ticlopidine and then start therapy with a COX-2 dence of congestive heart failure (CHF) in patients 65 years inhibitor, to use topical NSAID therapy (diclofenac)(22,23), or or older who have a history of heart disease is just as high as to implement therapy directly with either a short-acting opioid the incidence of UGI peptic ulcer complications(17,18). The if the patient only needs one or two doses of this medication incidence appears to be the highest with the use of piroxicam, per day, or a long-acting opioids(24,25) if more frequent dosing naproxen, and tenoxicam(18). In fact, when these NSAIDs are of a short-acting opioid is necessary.
used in patients with a history of heart disease, the odds ratio Consequently, the WHO analgesic ladder oversimplifi es of developing CHF is 25(19). Consequently, patients with either the management of OA pain in patients with complex co- chronic renal failure or increased plasma creatinine levels, morbidities which are typically present in the population af-those with a history of PUD or heart disease should not be fected by this disease. Additionally, the use of topical NSAIDs treated with NSAIDs. In contrast, it appears that celecoxib is not part of the algorithm as this form of therapy did not could be used in those patients with a history of heart disease, exist when the guidelines were drafted. These two situations as the incidence of CHF after one year of treatment, in a make the analgesic ladder obsolete and even dangerous in large scale observational study, was no different than those in the control group(19). However, the risk of thromboembolic phenomenon and myocardial infarction is still a concern, NEUROPATHIC PAIN
The other clinical situation to consider in patients with OA Current guidelines for the treatment of peripheral neuropathic is the co-administration of a mini-dose of aspirin (ASA) and pain(8-10) suggest the implementation of therapy with topical NSAIDs or COX-2 inhibitors. There is evidence that suggests lidocaine as the fi rst step. If this is not successful, and there that the co-administration of ASA and ibuprofen may result in is not a contraindication for the use of a tricyclic antidepres- acetylation of the serine 529 residue in the platelet that results sant (TCA), the addition of one of these agents is suggested. in >95% inhibition of thromboxane A2 (TXA2) production Alternatively, a dual re-uptake norepinephrine/serotonine and with this phenomenon, the loss of the anti-aggregation inhibitor may be used. If this combination is still not suc-effect of ASA in the platelets(20). It is not clear if this drug-drug cessful, then the use of an anticonvulsant is suggested, and if interaction may also occur with other NSAIDs, but al least in despite the use of these three agents at maximum doses is not theory, based on the mechanism of action, this could occur. successful, then the use of an opioid or tramadol is suggested. Moreover, there is evidence that co-administering a mini-dose Current guidelines for the management of central pain suggest of ASA and celecoxib(15) or lumirocoxib(21) may result in the following the same algorithm as that outlined for peripheral loss of the gastro-protective effects of COX-2 inhibitors. In neuropathic pain, with the exception that topical lidocaine is the case of celecoxib(15), patients not concomitantly receiv- ing ASA and celecoxib 400 mg twice daily had a statistically Consequently, the use of multiple adjuvants in the treat-
cant lower incidence of upper gastrointestinal (UGI) ment of neuropathic pain is indicated prior to implementing complications than those treated with non-specifi c NSAID therapy with opioids, but they are recognized as an important (naproxen 800 mg TID or diclofenac 75 mg BID) (0.44 component of a treatment plan. There is no data to suggest versus 1.27%, p = 0.04) and a signifi cant lower incidence of which opioid should be used when needed in these patients. complications and symptomatic ulcers (1.4 versus 2.91%, p = There have been suggestions, based on putative mechanisms 0.02). In contrast, patients who received ASA and celecoxib of action, that tramadol, tapentadol, or methadone would be 400 mg twice daily did not have neither a lower incidence better choices, but this superiority has not been demonstrated of UGI complications (2.01 versus 2.12%, p = 0.92) nor a in randomized clinical trials.
de Leon-Casasola OA. Opioids for the treatment of non-cancer pain IMPLEMENTING THERAPY
all other drugs are compared. Despite its clinical utility, the associated side effects led to attempts to develop molecules Understanding the pharmacokinetics and pharmacodynamics with similar analgesic action without the management chal- of opioids is imperative to providing patients with effective lenges(29). Over the last hundred years, numerous opiate drugs pain relief and avoiding adverse effects, such as sedation, have been synthesized and the vast majority falls into the nausea, and vomiting. The clinician’s efforts should be di- mu category; ie, they target the mu opioid receptor (MOR). rected at producing opioid plasma concentrations within the Initially, all mu opioids were thought to act through a single therapeutic window to avoid side effects that occur when drug class of opioid receptors, but subsequent research has identi- concentrations rise above those necessary for pain relief and fi ed genetic locations for several mu opioid receptor subtypes. loss of effi cacy when plasma levels are too low(26). It is recom- To date, at least 25 variants of the mu receptor have been mended to try to open the therapeutic window to decrease the identifi ed in mice, 8 in rats, and 11 in humans(30). Although incidence of sedation, nausea and vomiting that may occur in mu opioids share many pharmacological characteristics, there up to 30% of the patient when fi rst exposed to opioid therapy by prescribing a small dose of a long-acting opioid and then The concept of multiple mu receptors may help explain allowing the patient free access to a short-acting opioid(26). the variability in individual response to various opioids, the After two weeks of therapy, acute tolerance will typically de- differences in side effects among patients, incomplete cross velop, and with that, the therapeutic window widens, allowing tolerance among various mu opioid analgesics, and the clinical patients to tolerate higher doses of controlled released opioids utility of opioid rotation(3,26,28). Opioid rotation is now a widely with a lower incidence of these side effects(26).
accepted approach to poorly responsive pain patients in whom a neuropathic pain component has been adequately treated or BREAKTHROUGH PAIN
ruled out. If side effects with one opioid are signifi cant, an improved balance between analgesia and side effects might Breakthrough pain is defi ned as a transitory increase of more be achieved by changing to an equivalent dose of an alternate severe pain over relatively well-controlled baseline pain(27,28). opioid(26). Rotation between 2 or 3 opioids is often required to The reported incidence of breakthrough pain ranges between obtain satisfactory long-term pain control(31). A systematic re- 16% and 95% in patients with persistent pain(28). There are three view of existing literature on opioid rotation performed in 2006 types of breakthrough pain: end-of-dose failure, incidental pain, found that opioid switching results in clinical improvements and spontaneous/idiopathic pain(28). End-of-dose failure occurs in greater than 50% of patients with chronic pain who experi- when plasma concentrations fall below the therapeutic window. ence a poor response to one opioid(32). However, an important In order to avoid end-of-dose failure, the dosing interval should problem raised in the opioid literature is the conversion rate be decreased. It is important to talk to patients about patterns among the various opioid medications. Most conversion data of breakthrough pain in relation to the time of administration presented in reference tables are derived from older studies of the long-acting opioid to determine if end-of-dose failure is that were not designed for determining relative potencies(32). responsible for the appearance of breakthrough pain.
Yet, an understanding of equianalgesic doses is important Incidental and «true» breakthrough pain both occur despite when both titrating long-acting opioids and performing opioid appropriate opioid plasma concentrations. True breakthrough rotations. One practical approach is the «rule of 2»(26) (Table pain rises quickly in intensity and it is severe, occurring in I). Assuming a morphine dose of 100 mg/24 h and dividing patients whose pain was previously well controlled. It usually it by two, one arrives at a dose equivalent of 50 mg/24 h for lasts between 30 and 45 minutes before subsiding. A medication oxycodone/hydrocodone. Dividing it by four, one reaches with a rapid onset of action such as oral transmucosal fentanyl the fentanyl (25 μg/h) and oxymorphone (25 mg/24 h) dose or a fentanyl buccal tablet is needed to control this type of equivalents. Dividing it by eight, one obtains the equianalgesic pain, assuming that the pain is somatic in nature. In contrast, dose of 12 mg/24 h for hydromorphone. This method allows if the pain is neuropathic, it is unlikely that these alternative therapeutic options will be useful. Overall, when dealing with
Table I. Equianalgesic doses: Rule of two
breakthrough pain, it is important to determine fi rst, whether (Based on a morphine dose of 100 mg/24 h)(26).
the pain is somatic, visceral or neuropathic, and then if it is due to end-of-dose failure or incidental and treat appropriately.
The largest groups of opioids are the morphine-like agonists. Morphine remains a prototypic opioid analgesic against which Volumen 35, Suplemento 1, abril-junio 2012 de Leon-Casasola OA. Opioids for the treatment of non-cancer pain for relatively quick conversions. Although on the conservative or the gel form. However, reduced sex hormones are more side, these quick conversions should place the patient’s plasma problematic in women because of the increased risk of breast levels in the therapeutic range. However, the patient should be cancer after estrogen/progesterone replacement. Thus, a con- contacted within a day or two to determine if further titration sult with an endocrinologist may be warranted to address the is required. Although methadone is a very effective, and in- risk of osteoporosis with the use of bisulphonates, calcium expensive, medication, it provides a unique challenge because there are no good dosing guidelines and no easy conversion Opioid abuse and diversion: Based on the 2003 position
rates(32,33). Although there are several conversion protocols for paper from the College on Problems of Drug Dependence, methadone, for patients on a moderate opioid dose (400 mg of there is a «need to strike a balance between risk management morphine), we usually convert to 10 mg of methadone every 8 strategies to prevent and deter prescription opioid abuse hours for the fi rst two weeks of treatment and then titrate the and the need for physicians and patients to have appropri- dose, based on pain scores, psychosocial functioning, rescue ate access to opioid pharmaceuticals for the treatment of opioid use, etc. If the patient is on higher opioid doses, the pain»(38). Although opioids should be a tool in the analgesic starting methadone dose is 20 mg every 8 hours. Patients on armamentarium, it is essential that all health care providers methadone need to be monitored closely. One study found a approach pain management using opioids with the necessary correlation between the daily dose of methadone and the QTc due diligence, including a complete initial evaluation, fol- interval in 17 patients who experienced torsade de pointes(34). lowed by appropriate monitoring (random urine testing), and Of note, the relationship persisted after adjusting for the clinical documentation throughout treatment. At the outset of therapy variables known to be associated with QT-segment prolonga- with opioids, obtaining a signed agreement should be con- tion. In patients who receive methadone doses greater than sidered wherein the patient’s expectations and the clinician’s 100 mg per day, it is imperative that baseline EKG testing be performed and then repeated every 3 months(26). In addition, Likewise, universal precautions should be implemented if patients are receiving medications known to prolong the for other drug with a misuse potential such as certain anti-QTc segment, a consideration to switch to a different opioid depressants and psychotropic agents (i.e., benzodiazepines). Misuse includes usage of inappropriate drug combinations In November 2006, the FDA released an alert about this due to poor patient education or misinformation, as well as information (FDA, 2006). The alert resulted in the addition abuse and diversion. Appropriate education in an understand- of a black box warning to the product labeling for methadone able vernacular is essential to successful pain management. manufactured as Dolophine® Hydrochloride CII (Roxane A strong predictor of the potential to opioid misuse is other Laboratories, Columbus, OH).
medication misuse, or alcohol and/or illicit drug abuse(39). Este documento es elaborado por Medigraphic Because patient reporting of both prescribed and other drugs IMPORTANT CONSIDERATIONS IN THE
is highly unreliable at best, and because in the United Stated, LONG-TERM USE OF OPIOIDS
43% of patients on long-term opioid therapy misuse their medications, routine urine toxicity screens for a wide range There are four long-term concerns with the use of opioids: of substances are considered the cornerstone of pharmaco-endocrine changes, opioid abuse and diversion, those related logical vigilance at this point(39,40). When opioid therapy is to the central effects and metabolism of these agents, and initiated, and there is a high index of suspicion for opioid opioid-induced hyperalgesia.
abuse, a baseline urine drug screen can be used to assess if Endocrine changes: Long-term opioid use decreases there has been any drug misuse, even before opioid therapy
cortisol levels, which may be why patients experience las- is begun. Evaluations of patients should also involve noting situde and lack of energy after long periods of therapy. It and documenting slurred speech, sleeping, or weaving while is important not to confuse these symptoms with those seen walking, including observations gathered before the patient when opioid therapy is implemented acutely(26). The diagno- has even entered the examination room.
sis is made by performing an adrenocorticotropin (ACTH) Using tools to interview and collect observations of patients
are another important strategy to monitoring and documenting sideration to withdrawing opioid therapy or implementing a patient’s management with opioids (Table II). Screening corticosteroid replacement therapy is indicated. Additionally, tools can provide information that can lead to the detection of opioids decrease prolactin, luteinizing hormone (LH), follicle early warning signs of drug misuse and indicate the need for stimulating hormone (FSH), testosterone, and estrogen levels, more thorough monitoring and in-person patient interactions. which in turn can cause sexual impotence and eventually These instruments can help indicate which patients may be osteoporosis(3,36,37). This problem can easily be overcome more prone to non-adherence to therapeutic protocols, as well in men by prescribing testosterone in either intramuscular as to demonstrate due diligence in monitoring prescription de Leon-Casasola OA. Opioids for the treatment of non-cancer pain Table II. Tools for assessing drug misuse potential.
poor stress management and deteriorating work and/or home environments. These patients often self-medicate to «deal» with their stressors, as well as to control their pain. In fact, • Aberrant behaviors identified by clinicians according to a long-term follow-up study, patients with high PMQ scores were 2.6 times more likely to have a known • Checklist of risk behaviors (Chabal, Erjavec, et al, substance-abuse problem, 3.2 times more likely to request early refi lls of prescription medications, and 2.3 times more • Prescription drug use questionnaire (PDUQ; likely to drop out of treatment than patients with initially low • Physician opioid therapy questionnaire (POTQ; PMQ scores(45). Furthermore, patients who completed an interdisciplinary pain management program had signifi cantly • Addiction behaviors checklist (ABC; Wu et al, lower PMQ scores 6 months following discharge, compared to 2006) those patients who discontinued the treatment. Patients with PMQ scores over 32.83 should be closely monitored, as they • The screening tool for addiction risk (STAR; Fried- have a high potential for misusing controlled substances. The PMQ can be a good resource that can be combined with other • The screening instrument for substance abuse assessment techniques in order to gather a full understanding of a chronic pain patient, leading to better individualization • Screener and opioid assessment for patients with pain (SOAPP; Butler et al, 2004) of therapy, and ultimately, better outcomes.
• Opioid risk tool (ORT; Webster & Webster, 2005) Other important considerations: The use of morphine
• Current opioid misuse measure (COMM; Butler et in patients with severe renal or hepatic insuffi ciency is not advisable because they may experience myoclonus and/or • Pain medication questionnaire (PMQ; Adams et hyperalgesia due to morphine-3-glucoronide (M3G) accumu- lation. M3G, in contrast to the other metabolite of morphine, morphine-6-glucoronide (M6G), is neurotoxic(26).
Moreover, opioids in general should be used with caution in patients with Addison’s disease, hypothyroidism, prostatic use for potential US Food and Drug Administration audits. hypertrophy, or urethral stricture, and in elderly or debilitated In addition, the results from these tools, such as the Pain patients(26).
Medication Questionnaire (PMQ), can be used to tailor the Another important consideration when administering opi- treatment program to the specifi c needs of patients. Still, they oids is the effect on cognitive function(31). Side effects such can be limited by their time-consuming nature, psychometric as sedation, dizziness, and mental clouding interfere with (un)reliability, and specifi city for only one type of alcohol or activities that demand alertness, especially driving. Although drug abuse (i.e., non-generalizable results).
driving is not advisable at the beginning of treatment, studies The variety of pain medication questionnaires available have shown that cognitive function, including the ability to is listed in table II. For example, chronic pain patients being drive and operate machinery is often adequate in patients tak- considered for long-term opioid therapy can be administered ing stable, moderate doses of opioids for chronic pain(46,47).
the Screener and Opioid Assessment for Patients with Pain When indicated and an opioid drug regimen is chosen, it is (SOAPP) or the Opioid Risk Tool (ORT) to screen for sub- important to be cognizant of the potential for drug-drug inter- stance abuse potential(41,42). The SOAPP is a 14-item tool with actions, as many opioids are metabolized by the enzymes that established reliability and predictive validity. Alternatively, modify and break down 40 to 50% of all medications. These the Diagnosis, Intractability, Risk, and Effi cacy (DIRE) score are the cytochrome P450 (CYP450) isoenzymes, and those can be used to predict whether a chronic non-cancer pain primarily involved with opioid metabolism are the CYP2D6, patient will achieve effective analgesia and adhere to a long- CYP2B6 (methadone), and CYP3A4 (fentanyl) systems(48,49). term opioid maintenance treatment regimen(43).
Tramadol, oxycodone, hydrocodone, and codeine are con-
The PMQ is another self-report measure that can be verted to active metabolites by CYP2D6. Therefore, drugs that administered quickly to broadly survey a patient’s misuse inhibit this enzyme will decrease their effects(50,51). In addi-potential for a range of pain medication types prescribed tion, other commonly used medications, including fl uoxetine, for chronic pain. Higher PMQ scores have a positive asso- haloperidol, and paroxetine, can inhibit CYP2D6 function ciation with measures of substance abuse, psychopathology, resulting in a lack of pain relief(52). In constrast, morphine, and physical/life-functioning(44); in other words, high-risk hydromorphone, and oxymorphone are not metabolized by the patients tend to have diffi culties controlling their medication CYP450 enzymes, and therefore, can generally be prescribed use concurrent with signifi cant psychosocial issues, such as with medications metabolized by that enzyme family(50).
Volumen 35, Suplemento 1, abril-junio 2012 de Leon-Casasola OA. Opioids for the treatment of non-cancer pain Opioid induced hyperalgesia: Sustained exposure to mented(56-58). For advanced severe cases of opioid-induced
opioids may result in increase sensitivity to pain, potentially hyperalgesia, high-dose intravenous dexamethasone (a load- by enhancing the descending facilitatory infl uence of the ing dose of 20 mg, followed by a course of 6-8 mg every 6 brain on pain transmission at the spinal cord level(53). This hours for a week) can be used effectively alongside other phenomenon, known as opioid-induced hyperalgesia, can adjuvant therapies and acetaminophen, while progressively be an outcome of very aggressive opioid dose titration(54). tapering opioid doses. Dexamethasone decreases neuropep- Likewise, the perioperative use of remifentanyl and fentanyl tides, such as calcitonin gene-related peptide (CGRP) and have been shown to have a higher risk, but all opioids, even substance P, that are involved in neurogenic infl ammation and methadone, have the capacity to induce this phenomenon opioid-induced hyperalgesia, and it induces the production when rapidly titrated to higher doses in patients with chronic of kynurenic acid, a post-synaptic NMDA antagonist(56,57).
pain(55). Pronociception may also result from spinal sensiti-zation due to inappropriate increased brainstem excitatory CONCLUSIONS
infl uences, involving spinal cholecystokinin and dynorphin, descending facilitation of the glutamatergic system, and sub- Not all patients respond to analgesic regimens, including stance P wind-up (increased central sensitization in response opioid treatments. For these select patients, the following to sustained input from nociceptive afferents)(53-55).
clinical scenarios should be considered and their treatment Clinically, it is very important to distinguish between correspondingly adjusted: opioid tolerance, opioid-induced opioid tolerance and opioid-induced pain sensitivity because, hyperalgesia, an alternative disease processes such as myo- despite having similar presentations, they require opposite fascial pain, and opioid misuse. Additionally, each patient’s management approaches(55). In both cases, patients present unique genetic background can infl uence the effectiveness with worsening pain. However, in the case of opioid-induced and side effects of an analgesic regimen. Therefore, therapies hyperalgesia, the pain intensity is increased above the level of need to be individualized for each patient in order to maximize the preexisting pain, despite the absence of disease progres- opioid analgesic effects and minimize side effects, including sion while opioid doses are titrated up(55). Also, with opioid- discontinuing or rotating opioids when appropriate. Given the induced hyperalgesia, the pain is more diffuse, often affecting potential for metabolic issues and drug interactions, and the areas beyond the original pain distribution. Managing opioid availability of multiple analgesic options, when prescribing tolerance with a trial of opioid dose escalation can appropri- opioids it is also important to use strategies that minimize drug ately control the pain, whereas opioid-induced hyperalgesia interactions. Especially for individuals on multidrug regimens, can be exacerbated with increasing opioid doses(55). In the such as older adults, an opioid that is not metabolized by the latter case, opioid doses should be signifi cantly reduced and P450 enzyme system, such as morphine, hydromorphone or acetaminophen and dexamethasone therapy should be imple- oxymorphone, may be more suitable than other choices.
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Volumen 35, Suplemento 1, abril-junio 2012


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