Flawed methodology undermines conclusions about opioid-induced pleasure: implications for psychopharmacology
2019; Elsevier BV; Volume: 124; Issue: 3 Linguagem: Inglês
10.1016/j.bja.2019.10.006
ISSN1471-6771
Autores Tópico(s)Pain Mechanisms and Treatments
ResumoEditor—Interdisciplinary psychopharmacological investigations have provided decades of important insights on how drugs affect behaviour. Researchers in pharmacology, medicine, and neuroscience integrate rich tools from disparate fields, including experimental psychology, pharmacodynamics, and statistics, to understand how drugs affect reward and decision-making,1Pessiglione M. Seymour B. Flandin G. Dolan R.J. Frith C.D. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans.Nature. 2006; 442: 1042-1045Crossref PubMed Scopus (968) Google Scholar, 2Eikemo M. Løseth G.E. Johnstone T. Gjerstad J. Willoch F. Leknes S. Sweet taste pleasantness is modulated by morphine and naltrexone.Psychopharmacology (Berl). 2016; 233: 3711-3723Crossref PubMed Scopus (31) Google Scholar, 3Eikemo M. Biele G. Willoch F. Thomsen L. Leknes S. Opioid modulation of value-based decision-making in healthy humans.Neuropsychopharmacology. 2017; 42: 1833-1840Crossref PubMed Scopus (15) Google Scholar and how beliefs4Benedetti F. Maggi G. Lopiano L. et al.Open versus hidden medical treatments: the patient's knowledge about a therapy affects the therapy outcome.Prev Treat. 2003; 6: 1-19Crossref Google Scholar, 5Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3 (70ra14)Crossref PubMed Scopus (430) Google Scholar, 6Atlas L. Wielgosz J. Whittington R. Wager T. Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect.Psychopharmacology (Berl). 2014; 231: 813-823Crossref PubMed Scopus (22) Google Scholar and context7Söderpalm A. Nikolayev L. de Wit H. Effects of stress on responses to methamphetamine in humans.Psychopharmacology (Berl). 2003; 170: 188-199Crossref PubMed Scopus (38) Google Scholar,8Kirkpatrick M.G. de Wit H. MDMA: a social drug in a social context.Psychopharmacology (Berl). 2015; 232: 1155-1163Crossref PubMed Scopus (15) Google Scholar influence drug effects. Proper integration of these tools leads to knowledge that has real potential to improve health and well-being. Likewise, improper methodology can undermine research and lead to flawed conclusions. A new study by Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar concluded that the fast-acting μ-opioid agonist remifentanil induces pleasure in healthy young men. Initial pleasure and euphoria from drugs are proposed to increase subsequent addiction risk.10de Wit H. Phillips T.J. Do initial responses to drugs predict future use or abuse?.Neurosci Biobehav Rev. 2012; 36: 1565-1576Crossref PubMed Scopus (106) Google Scholar In light of the opioid epidemic, it is more important than ever to understand how opioid drugs influence and affect behaviour. Unfortunately, the work by Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar failed to account for the basic tenets of experimental design and analysis (see Fig. 1), which therefore undermines this study's ability to provide these much needed insights. Here, we outline six important considerations in interdisciplinary pharmacology studies, and use the study of Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar to illustrate the importance of methodological rigour.(1)The need for proper blinding: one of the fundamental tenets of psychopharmacology is to study drug effects whilst controlling for expectations and other non-specific factors (i.e. placebo effects). Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar administered remifentanil, saline, or naloxone in a single-blind design. Such designs can introduce bias attributable to physician/experimenter expectations. For instance, when physicians believed they might be administering a potent painkiller, blinded patients reported placebo analgesia corresponding to 10% of the scale relative to patients whose doctors believed their patients would receive placebo or naloxone.11Gracely R. Dubner R. Deeter W. Wolskee P. Clinicians' expectations influence placebo analgesia.Lancet. 1985; 325: 43Abstract Scopus (210) Google Scholar Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar reported a pleasantness rating difference of 5% between remifentanil and saline. This difference could therefore be entirely accounted for by experimenter expectations.Blinding is critical for reducing experimenter influences on patient outcomes. Both remifentanil and naloxone can be administered in a double-blind manner,12Gospic K. Gunnarsson T. Fransson P. Ingvar M. Lindefors N. Petrovic P. Emotional perception modulated by an opioid and a cholecystokinin agonist.Psychopharmacology (Berl). 2008; 197: 295-307Crossref PubMed Scopus (32) Google Scholar, 13Buchel C. Miedl S. Sprenger C. Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system.eLife. 2018; 7e39648Crossref PubMed Scopus (20) Google Scholar, 14Berna C. Leknes S. Ahmad A.H. Mhuircheartaigh R.N. Goodwin G.M. Tracey I. Opioid-independent and opioid-mediated modes of pain modulation.J Neurosci. 2018; 38: 9047Crossref PubMed Scopus (16) Google Scholar indicating that this would have been possible here. When double blinding is not possible, researchers must report the rationale and make every effort to avoid experimenter effects (see Kaptchuk and colleagues15Kaptchuk T.J. Kelley J.M. Conboy L.A. et al.Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome.BMJ. 2008; 336: 999-1003Crossref PubMed Scopus (813) Google Scholar). For example, other (blinded) test personnel can conduct testing and communication with the participants, or the experimenter's behaviour and language can be standardised across participants. After the study, investigators can statistically account for potential factors, such as experimenter expectation, and ensure that data are analysed in a blinded manner. Study blinding and precautionary steps should always be reported in papers. Somewhat alarmingly, single-blind designs without these precautions still appear common in psychopharmacology (e.g. see Jones and colleagues16Jones J.D. Sullivan M.A. Manubay J.M. et al.The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users.Physiol Behav. 2016; 159: 33-39Crossref PubMed Scopus (15) Google Scholar and Shram and colleagues17Shram M.J. Silverman B. Ehrich E. Sellers E.M. Turncliff R. Use of remifentanil in a novel clinical paradigm to characterize onset and duration of opioid blockade by samidorphan, a potent μ-receptor antagonist.J Clin Psychopharmacol. 2015; 35: 242-249Crossref PubMed Scopus (29) Google Scholar). (2)Counterbalancing to reduce order effects: Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar administered drugs in a fixed order. Fixed-order designs can reduce the number of test sessions required (e.g. in studies using cumulative doses).16Jones J.D. Sullivan M.A. Manubay J.M. et al.The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users.Physiol Behav. 2016; 159: 33-39Crossref PubMed Scopus (15) Google Scholar However, these designs introduce confounds with effects of time, which become particularly problematic when researchers do not carefully consider pharmacokinetics and pharmacodynamics (see Point 5 below). Studies should make every effort to counterbalance drug order, or use a between-subject design to avoid confounds. Adding a placebo-only session to document time effects is another workable approach.16Jones J.D. Sullivan M.A. Manubay J.M. et al.The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users.Physiol Behav. 2016; 159: 33-39Crossref PubMed Scopus (15) Google Scholar For affective stimuli, such as the videos rated by the participants of Heiskanen and colleagues,9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar abundant evidence suggests that pleasantness ratings decrease over time (e.g. see Leventhal and colleagues18Leventhal A.M. Martin R.L. Seals R.W. Tapia E. Rehm L.P. Investigating the dynamics of affect: psychological mechanisms of affective habituation to pleasurable stimuli.Motiv Emot. 2007; 31: 145-157Crossref Scopus (26) Google Scholar and Shrout and colleagues19Shrout P.E. Stadler G. Lane S.P. et al.Initial elevation bias in subjective reports.Proc Natl Acad Sci U S A. 2018; 115: E15-E23Crossref PubMed Scopus (53) Google Scholar). For painful stimuli, both habituation and sensitisation are known.20Jepma M. Jones M. Wager T.D. The dynamics of pain: evidence for simultaneous site-specific habituation and site-nonspecific sensitization in thermal pain.J Pain. 2014; 15: 734-746Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar As remifentanil was always administered first followed by saline and then naloxone, the study of Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar cannot separate the effects modulated by the μ-opioid receptor system from those induced simply by the passage of time.(3)Construct validity and measurement of affect: Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar concluded that 'the opioid agonist remifentanil increases subjective pleasure', yet they did not report drug effects on mood. Instead, they collected ratings of valence and arousal in response to 30 brief films of varying valence, which were played without sound. Ratings ranged from strong pleasure to strong displeasure. However, valence is distinct from mood. Were the participants rating how they felt, or were they rating the emotional content of the film itself?Previous studies have reported that remifentanil increased ratings of stimulus pleasantness in healthy volunteers for neutral12Gospic K. Gunnarsson T. Fransson P. Ingvar M. Lindefors N. Petrovic P. Emotional perception modulated by an opioid and a cholecystokinin agonist.Psychopharmacology (Berl). 2008; 197: 295-307Crossref PubMed Scopus (32) Google Scholar and positive6Atlas L. Wielgosz J. Whittington R. Wager T. Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect.Psychopharmacology (Berl). 2014; 231: 813-823Crossref PubMed Scopus (22) Google Scholar but not for negative International Affective Picture System pictures.6Atlas L. Wielgosz J. Whittington R. Wager T. Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect.Psychopharmacology (Berl). 2014; 231: 813-823Crossref PubMed Scopus (22) Google Scholar,12Gospic K. Gunnarsson T. Fransson P. Ingvar M. Lindefors N. Petrovic P. Emotional perception modulated by an opioid and a cholecystokinin agonist.Psychopharmacology (Berl). 2008; 197: 295-307Crossref PubMed Scopus (32) Google Scholar Other opioid agonists, such as morphine2Eikemo M. Løseth G.E. Johnstone T. Gjerstad J. Willoch F. Leknes S. Sweet taste pleasantness is modulated by morphine and naltrexone.Psychopharmacology (Berl). 2016; 233: 3711-3723Crossref PubMed Scopus (31) Google Scholar,21Chelnokova O. Laeng B. Eikemo M. et al.Rewards of beauty: the opioid system mediates social motivation in humans.Mol Psychiatry. 2014; 19: 746-747Crossref PubMed Scopus (76) Google Scholar and buprenorphine,22Bershad A.K. Ruiz N.A. de Wit H. Effects of buprenorphine on responses to emotional stimuli in individuals with a range of mood symptomatology.Int J Neuropsychopharmacol. 2018; 21: 120-127Crossref PubMed Scopus (13) Google Scholar,23Bershad A.K. Seiden J.A. de Wit H. Effects of buprenorphine on responses to social stimuli in healthy adults.Psychoneuroendocrinology. 2016; 63: 43-49Crossref PubMed Scopus (33) Google Scholar also increased the pleasantness ratings of rewarding stimuli. Conversely, opioid blockade was reported to decrease stimulus pleasantness whilst leaving mood unaltered.13Buchel C. Miedl S. Sprenger C. Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system.eLife. 2018; 7e39648Crossref PubMed Scopus (20) Google ScholarTo make conclusions about subjective pleasure, studies should directly measure mood and drug-induced pleasure/euphoria independent of stimulus valence. Interestingly, studies that have directly measured mood and pleasure in non-opioid users contradict the conclusions of Heiskanen and colleagues.9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar In contrast to the pervasive view that opioid agonists induce a state of pleasure, healthy, pain-free participants treated with morphine,24Zacny J. Lichtor S. Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers.Psychopharmacology (Berl). 2008; 196: 105-116Crossref PubMed Scopus (64) Google Scholar oxycodone,25Wardle M.C. Fitzgerald D.A. Angstadt M. Rabinak C.A. de Wit H. Phan K.L. Effects of oxycodone on brain responses to emotional images.Psychopharmacology (Berl). 2014; 231: 4403-4415Crossref PubMed Scopus (10) Google Scholar or remifentanil often report disliking the drug effects. One placebo-controlled double-blind randomised trial even reported that remifentanil dose-dependently increased dysphoria in healthy young men.26Wagner K. Valet M. Kochs E. Kriner M. Tölle T. Sprenger T. The μ-opioid receptor agonist remifentanil induces acute dysphoria irrespective of its analgesic properties.J Psychopharmacol (Oxf). 2010; 24: 355-361Crossref PubMed Scopus (10) Google Scholar Reconciling this work with the findings of Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar requires measurement of mood, subjective emotional state, and hedonic experiences, rather than simply relying on valence ratings of emotional stimuli. (4)Test population and generalisability: the choice of test population is also key. Despite increasing recognition in neuroscience that females are no more variable than males,27Shansky R.M. Are hormones a "female problem" for animal research?.Science. 2019; 364: 825-826Crossref PubMed Scopus (108) Google Scholar many studies still limit participants—and thereby generalisability—to healthy young men.3Eikemo M. Biele G. Willoch F. Thomsen L. Leknes S. Opioid modulation of value-based decision-making in healthy humans.Neuropsychopharmacology. 2017; 42: 1833-1840Crossref PubMed Scopus (15) Google Scholar,9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar,13Buchel C. Miedl S. Sprenger C. Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system.eLife. 2018; 7e39648Crossref PubMed Scopus (20) Google Scholar,26Wagner K. Valet M. Kochs E. Kriner M. Tölle T. Sprenger T. The μ-opioid receptor agonist remifentanil induces acute dysphoria irrespective of its analgesic properties.J Psychopharmacol (Oxf). 2010; 24: 355-361Crossref PubMed Scopus (10) Google Scholar Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar provided no rationale for limiting their study population to males, and both remifentanil and naloxone have been safely delivered in women in numerous previous studies.(5)Appropriate choice of drugs, dosages, and timing of experimental designs: Drugs can change outcomes indirectly via mood or side-effects. For instance, a sedated participant may fail to attend to the task. Drug doses and administration methods must be selected carefully to optimise the outcome of interest whilst minimising the influence of unwanted side-effects. The experimental design must also be guided by pharmacokinetics and pharmacodynamics to avoid carry-over effects and drug interactions.Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar reported the effects of naloxone, which was used to putatively block opioid receptors and probe functions believed to rely on endogenous opioid activation. The authors wrote that the dose of naloxone used in their study was smaller than that of some previous studies, which is true. Their participants received ∼3% of the dose typically used to induce full blockade of μ-opioid receptors,13Buchel C. Miedl S. Sprenger C. Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system.eLife. 2018; 7e39648Crossref PubMed Scopus (20) Google Scholar,14Berna C. Leknes S. Ahmad A.H. Mhuircheartaigh R.N. Goodwin G.M. Tracey I. Opioid-independent and opioid-mediated modes of pain modulation.J Neurosci. 2018; 38: 9047Crossref PubMed Scopus (16) Google Scholar corresponding to μ-opioid receptor blockade of only ∼20%.28Mayberg H.S. Frost J.J. Opiate receptors.in: Frost J.J. Wagner H.N. Quantitative imaging: neuroreceptors, neurotransmitters, and enzymes. Raven Press, New York1990: 81-95Google Scholar Whilst it is possible that such a modest blockade suffices to reveal the effects of the endogenous system on behaviour, 80% of the participants' μ-opioid receptors remain available for endogenous activation. A null effect from low-dose antagonism, as reported, is therefore uninformative even with appropriate statistics (see Point vi). This type of dosing issue is widespread in the literature. The range of opioid antagonist doses and administration methods in pain studies29Werner M.U. Pereira M.P. Andersen L.P. Dahl J.B. Endogenous opioid antagonism in physiological experimental pain models: a systematic review.PLoS One. 2015; 10e0125887Crossref PubMed Scopus (9) Google Scholar spans from 3% to more than 200% of the dose required for the so-called full blockade (90–100% occupancy). Doses that are too low or too high hamper interpretability. Small antagonist doses leave most receptors unoccupied, and very large doses introduce confounds from drug binding at other sites (e.g. κ- and δ-opioid receptors).Importantly, drugs are not delivered in isolation in within-subject study designs. When multiple drugs or doses are administered to a study participant, it is essential that the pharmacokinetic and pharmacodynamic properties of the drug are taken into account. For instance, the 10 min washout period used is unlikely to result in complete washout of drug, as complete elimination requires from five to 10 times a drug's elimination half-life.30Byers J.P. Sarver J.G. Pharmacokinetic modeling.in: Hacker M. Bachmann K. Messer W. Pharmacology: Principles and Practice. Academic Press, 2009Crossref Scopus (15) Google Scholar The half-life of remifentanil is 6–30 min,31Minto C.F. Schnider T.W. Egan T.D. et al.Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.Anesthesiology. 1997; 86: 10-23Crossref PubMed Scopus (894) Google Scholar, 32Egan T.D. Huizinga B. Gupta S.K. et al.Remifentanil pharmacokinetics in obese versus lean patients.Anesthesiology. 1998; 89: 562-573Crossref PubMed Scopus (216) Google Scholar, 33Greenblatt D.J. Elimination half-life of drugs: value and limitations.Annu Rev Med. 1985; 36: 421-427Crossref PubMed Scopus (65) Google Scholar, 34Kapila A. Glass P.S. Jacobs J.R. et al.Measured context-sensitive half-times of remifentanil and alfentanil.Anesthesiology. 1995; 83: 968-975Crossref PubMed Scopus (343) Google Scholar, 35Egan T.D. Lemmens H.J. Fiset P. et al.The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers.Anesthesiology. 1993; 79: 881-892Crossref PubMed Scopus (477) Google Scholar, 36Glass P.S. Hardman D. Kamiyama Y. et al.Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B).Anesth Analg. 1993; 77: 1031-1040Crossref PubMed Google Scholar, 37Westmoreland C.L. Hoke J.F. Sebel P.S. Hug Jr., C.C. Muir K.T. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery.Anesthesiology. 1993; 79: 893-903Crossref PubMed Scopus (331) Google Scholar meaning that the drug is only completely out of the system after 0.5–2.5 h. Therefore, the drug is likely to still circulate in the next block when washout only lasts 10 min. This leads not only to confounds attributable to carry-over effects, but also potential interactions attributable to pharmacodynamics. For instance, in the study of Heiskanen and colleagues,9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar naloxone might be antagonising residual remifentanil effects, rather than modulating endogenous opioids as the authors assumed. Critically, both of these considerations are exacerbated with the fixed-order design, as it is impossible to disentangle carry-over effects and drug interactions from the task design. (6)Transparency and reproducibility in pharmacology: the methodological issues we outlined previously focus on proper study design in order to ensure valid conclusions from pharmacological studies. Our remaining concerns are motivated by a need for all areas of science to improve transparency and accountability in reporting results to achieve greater reproducibility. These efforts towards 'open science' have been motivated by researchers in psychology and medicine, but are increasingly recognised in multiple disciplines as being fundamental to identifying truth through research. In Heiskanen and colleagues,9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar details of statistical analyses and results were not reported. Nowhere in the paper did they report (a) which statistical tests were used to compare responses, (b) which statistical software was used, (c) statistical test outcomes (i.e. T- or F-statistics, P-values, or the study's alpha level), or (d) effect sizes or descriptive statistics. For example, the authors did not report how sample size was determined, or whether they have adequate power and sensitivity to compare their conditions. There is also increasing recognition that, when interpreting a null finding, appropriate analyses, such as equivalence testing or a Bayesian approach, are necessary. A lack of transparency about analyses and results undermines the utility of any study in efforts towards reproducibility, such as meta-analysis. In sum, the conclusions of Heiskanen and colleagues9Heiskanen T. Leppä M. Suvilehto J. et al.The opioid agonist remifentanil increases subjective pleasure.Br J Anaesth. 2019; 122: e216-e219Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar are highly preliminary at best because of the fixed-order single-blind administration of low doses of opioid agonist and antagonist drugs in men and without adequate statistical reporting. In light of the role poor scientific practices may have had in facilitating the current opioid epidemic, it is imperative that adequate experimental control is used in future studies of opioids and other drug effects. The authors declare that they have no conflicts of interest. National Center for Complementary and Integrative Health to LYA: ZIA-AT-000030 ; European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 802885) to SL.
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