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19 pages, 1987 KiB

Open AccessArticle

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

by Shaul Schreiber, Lee Keidan and Chaim G. Pick

Int. J. Mol. Sci. 2023, 24(13), 11142; https://doi.org/10.3390/ijms241311142 - 6 Jul 2023

Cited by 1 | Viewed by 2553

Abstract

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction [...] Read more.

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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14 pages, 1097 KiB

Open AccessArticle

Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated by l-Tetrahydropalmatine

by Daria Oleinichenko, Soyon Ahn, Ru Song, Terrance P. Snutch and Anthony G. Phillips

Int. J. Mol. Sci. 2023, 24(10), 8872; https://doi.org/10.3390/ijms24108872 - 17 May 2023

Cited by 3 | Viewed by 1794

Abstract

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful [...] Read more.

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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25 pages, 1892 KiB

Open AccessArticle

Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy

by Daisuke Nishizawa, Tsutomu Mieda, Miki Tsujita, Hideyuki Nakagawa, Shigeki Yamaguchi, Shinya Kasai, Junko Hasegawa, Kyoko Nakayama, Yuko Ebata, Akira Kitamura, Hirotomo Shimizu, Tadayuki Takashima, Masakazu Hayashida and Kazutaka Ikeda

Int. J. Mol. Sci. 2023, 24(9), 8421; https://doi.org/10.3390/ijms24098421 - 8 May 2023

Cited by 1 | Viewed by 1657

Abstract

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays [...] Read more.

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D₁ receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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12 pages, 3227 KiB

Open AccessArticle

Distinct Profiles of Desensitization of µ-Opioid Receptors Caused by Remifentanil or Fentanyl: In Vitro Assay with Cells and Three-Dimensional Structural Analyses

by Eiko Uezono, Yusuke Mizobuchi, Kanako Miyano, Katsuya Ohbuchi, Hiroaki Murata, Akane Komatsu, Sei Manabe, Miki Nonaka, Takatsugu Hirokawa, Keisuke Yamaguchi, Masako Iseki, Yasuhito Uezono, Masakazu Hayashida and Izumi Kawagoe

Int. J. Mol. Sci. 2023, 24(9), 8369; https://doi.org/10.3390/ijms24098369 - 6 May 2023

Cited by 2 | Viewed by 1545

Abstract

Remifentanil (REM) and fentanyl (FEN) are commonly used analgesics that act by activating a µ-opioid receptor (MOR). Although optimal concentrations of REM can be easily maintained during surgery, it is sometimes switched to FEN for optimal pain regulation. However, standards for this switching [...] Read more.

Remifentanil (REM) and fentanyl (FEN) are commonly used analgesics that act by activating a µ-opioid receptor (MOR). Although optimal concentrations of REM can be easily maintained during surgery, it is sometimes switched to FEN for optimal pain regulation. However, standards for this switching protocol remain unclear. Opioid anesthetic efficacy is decided in part by MOR desensitization; thus, in this study, we investigated the desensitization profiles of REM and FEN to MOR. The efficacy and potency during the 1st administration of REM or FEN in activating the MOR were almost equal. Similarly, in β arrestin recruitment, which determines desensitization processes, they showed no significant differences. In contrast, the 2nd administration of FEN resulted in a stronger MOR desensitization potency than that of REM, whereas REM showed a higher internalization potency than FEN. These results suggest that different β arrestin-mediated signaling caused by FEN or REM led to their distinct desensitization and internalization processes. Our three-dimensional analysis, with in silico binding of REM and FEN to MOR models, highlighted that REM and FEN bound to similar but distinct sites of MOR and led to distinct β arrestin-mediated profiles, suggesting that distinct binding profiles to MOR may alter β arrestin activity, which accounts for MOR desensitization and internalization. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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8 pages, 241 KiB

Open AccessCommunication

Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study

by Rikuhei Tsuchida, Daisuke Nishizawa, Ken-ichi Fukuda, Tatsuya Ichinohe, Kuniyuki Kano, Makoto Kurano, Kazutaka Ikeda and Masahiko Sumitani

Int. J. Mol. Sci. 2023, 24(8), 6986; https://doi.org/10.3390/ijms24086986 - 10 Apr 2023

Viewed by 1580

Abstract

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) [...] Read more.

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

12 pages, 1443 KiB

Open AccessArticle

Inhibitory Effects of a Novel μ-Opioid Receptor Nonpeptide Antagonist, UD-030, on Morphine-Induced Conditioned Place Preference

by Soichiro Ide, Noriaki Iwase, Kenichi Arai, Masahiro Kojima, Shigeru Ushiyama, Kaori Taniko and Kazutaka Ikeda

Int. J. Mol. Sci. 2023, 24(4), 3351; https://doi.org/10.3390/ijms24043351 - 8 Feb 2023

Cited by 3 | Viewed by 2057

Abstract

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the μ-opioid receptor (MOP), they have [...] Read more.

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the μ-opioid receptor (MOP), they have been used for the management of opioid use disorder. The utility of highly selective MOP antagonists remains to be evaluated. Here, we biologically and pharmacologically evaluated a novel nonpeptide ligand, UD-030, as a selective MOP antagonist. UD-030 had more than 100-fold higher binding affinity for the human MOP (K_i = 3.1 nM) than for δ-opioid, κ-opioid, and nociceptin receptors (K_i = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [³⁵S]-GTPγS binding assay showed that UD-030 acts as a selective MOP full antagonist. The oral administration of UD-030 dose-dependently suppressed the acquisition and expression of morphine-induced conditioned place preference in C57BL/6J mice, and its effects were comparable to naltrexone. These results indicate the UD-030 may be a new candidate for the treatment of opioid use disorder, with characteristics that differ from traditional medications that are in clinical use. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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11 pages, 432 KiB

Open AccessArticle

Splice-Site Variants in the Gene Encoding GABA-A Receptor Delta Subunit Are Associated with Amphetamine Use in Patients under Methadone Maintenance Treatment

by Yen-Feng Lin, Wen-Hai Chou, Tung-Hsia Liu, Chiu-Ping Fang, Hsiang-Wei Kuo, Po-Hsiu Kuo, Shih-Jen Tsai, Sheng-Chang Wang, Ren-Hua Chung, Hsiao-Hui Tsou, Andrew C. H. Chen and Yu-Li Liu

Int. J. Mol. Sci. 2023, 24(1), 721; https://doi.org/10.3390/ijms24010721 - 31 Dec 2022

Cited by 16 | Viewed by 1915

Abstract

Chronic opioid use disorder patients often also use other substances such as amphetamines. The gene-based analysis method was applied in the genomic database obtained from our previous study with 343 methadone maintenance treatment (MMT) patients. We found that the gene encoding gamma-aminobutyric acid [...] Read more.

Chronic opioid use disorder patients often also use other substances such as amphetamines. The gene-based analysis method was applied in the genomic database obtained from our previous study with 343 methadone maintenance treatment (MMT) patients. We found that the gene encoding gamma-aminobutyric acid type A receptors (GABA-A receptor) delta subunit isoforms (GABRD) was associated with amphetamine use in heroin dependent patients under MMT in Taiwan. A total of 15% of the 343 MMT patients tested positive for amphetamine in the urine toxicology test. Two genetic variants in the GABRD, rs2889475 and rs2376805, were found to be associated with the positive urine amphetamine test. They are located in the exon 1 of the splice variant and altered amino acid compositions (T126I, C/T, for rs2889475, and R252Q, G/A, for rs2376805). The CC genotype carriers of rs2889475 showed a four times higher risk of amphetamine use than those with TT genotype. The GG genotype carriers of rs2376805 showed a three times higher risk of amphetamine use than the AA genotype carriers. To our knowledge, this is the first report that demonstrated an association of the delta splice variant isoform in the GABA-A receptor with an increased risk of amphetamine use in MMT patients. Our results suggest that rs2889475 and rs2376805 may be indicators for the functional role and risk of amphetamine use in MMT patients. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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30 pages, 3866 KiB

Open AccessArticle

^αN-Acetyl β-Endorphin Is an Endogenous Ligand of σ1Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for σ2Rs in σ1R Oligomers

by Javier Garzón-Niño, Elsa Cortés-Montero, María Rodríguez-Muñoz and Pilar Sánchez-Blázquez

Int. J. Mol. Sci. 2023, 24(1), 582; https://doi.org/10.3390/ijms24010582 - 29 Dec 2022

Cited by 2 | Viewed by 2516

Abstract

The opioid peptide β-endorphin coexists in the pituitary and brain in its ^αN-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type [...] Read more.

The opioid peptide β-endorphin coexists in the pituitary and brain in its ^αN-acetylated form, which does not bind to opioid receptors. We now report that these neuropeptides exhibited opposite effects in in vivo paradigms, in which ligands of the sigma type 1 receptor (σ1R) displayed positive effects. Thus, ^αN-acetyl β-Endorphin reduced vascular infarct caused by permanent unilateral middle cerebral artery occlusion and diminished the incidence of N-methyl-D-aspartate acid-promoted convulsive syndrome and mechanical allodynia caused by unilateral chronic constriction of the sciatic nerve. Moreover, ^αN-acetyl β-Endorphin reduced the analgesia of morphine, β-Endorphin and clonidine but enhanced that of DAMGO. All these effects were counteracted by β-Endorphin and absent in σ1R^−/− mice. We observed that σ1Rs negatively regulate mu-opioid receptor (MOR)-mediated morphine analgesia by binding and sequestering G proteins. In this scenario, β-Endorphin promoted the exchange of σ2Rs by G proteins at σ1R oligomers and increased the regulation of G proteins by MORs. The opposite was observed for the ^αN-acetyl derivative, as σ1R oligomerization decreased and σ2R binding was favored, which displaced G proteins; thus, MOR-regulated transduction was reduced. Our findings suggest that the pharmacological β-Endorphin-specific epsilon receptor is a σ1R-regulated MOR and that β-Endorphin and ^αN-acetyl β-Endorphin are endogenous ligands of σ1R. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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20 pages, 1912 KiB

Open AccessArticle

µ-Opioid Receptors Expressed by Intrinsically Photosensitive Retinal Ganglion Cells Contribute to Morphine-Induced Behavioral Sensitization

by Nikolas Bergum, Casey-Tyler Berezin, Connie M. King and Jozsef Vigh

Int. J. Mol. Sci. 2022, 23(24), 15870; https://doi.org/10.3390/ijms232415870 - 14 Dec 2022

Cited by 2 | Viewed by 1695

Abstract

Opioid drugs are the most effective tools for treating moderate to severe pain. Despite their analgesic efficacy, long-term opioid use can lead to drug tolerance, addiction, and sleep/wake disturbances. While the link between opioids and sleep/wake problems is well-documented, the mechanism underlying opioid-related [...] Read more.

Opioid drugs are the most effective tools for treating moderate to severe pain. Despite their analgesic efficacy, long-term opioid use can lead to drug tolerance, addiction, and sleep/wake disturbances. While the link between opioids and sleep/wake problems is well-documented, the mechanism underlying opioid-related sleep/wake problems remains largely unresolved. Importantly, intrinsically photosensitive retinal ganglion cells (ipRGCs), the cells that transmit environmental light/dark information to the brain’s sleep/circadian centers to regulate sleep/wake behavior, express μ-opioid receptors (MORs). In this study, we explored the potential contribution of ipRGCs to opioid-related sleep/circadian disruptions. Using implanted telemetry transmitters, we measured changes in horizontal locomotor activity and body temperature in mice over the course of a chronic morphine paradigm. Mice lacking MORs expressed by ipRGCs (McKO) exhibited reduced morphine-induced behavioral activation/sensitization compared with control littermates with normal patterns of MOR expression. Contrastingly, mice lacking MORs globally (MKO) did not acquire morphine-induced locomotor activation/sensitization. Control mice also showed morphine-induced hypothermia in both the light and dark phases, while McKO littermates only exhibited morphine-induced hypothermia in the dark. Interestingly, only control animals appeared to acquire tolerance to morphine’s hypothermic effect. Morphine, however, did not acutely decrease the body temperature of MKO mice. These findings support the idea that MORs expressed by ipRGCs could contribute to opioid-related sleep/wake problems and thermoregulatory changes. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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Review

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18 pages, 1116 KiB

Open AccessReview

Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation

by Kazuo Nakamoto and Shogo Tokuyama

Int. J. Mol. Sci. 2023, 24(14), 11713; https://doi.org/10.3390/ijms241411713 - 20 Jul 2023

Cited by 3 | Viewed by 2522

Abstract

Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic [...] Read more.

Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. μ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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11 pages, 693 KiB

Open AccessReview

Therapeutic Potential of Orally Administered Rubiscolin-6

by Yusuke Karasawa, Kanako Miyano, Masahiro Yamaguchi, Miki Nonaka, Keisuke Yamaguchi, Masako Iseki, Izumi Kawagoe and Yasuhito Uezono

Int. J. Mol. Sci. 2023, 24(12), 9959; https://doi.org/10.3390/ijms24129959 - 9 Jun 2023

Cited by 2 | Viewed by 1721

Abstract

Rubiscolins are naturally occurring opioid peptides derived from the enzymatic digestion of the ribulose bisphosphate carboxylase/oxygenase protein in spinach leaves. They are classified into two subtypes based on amino acid sequence, namely rubiscolin-5 and rubiscolin-6. In vitro studies have determined rubiscolins as G [...] Read more.

Rubiscolins are naturally occurring opioid peptides derived from the enzymatic digestion of the ribulose bisphosphate carboxylase/oxygenase protein in spinach leaves. They are classified into two subtypes based on amino acid sequence, namely rubiscolin-5 and rubiscolin-6. In vitro studies have determined rubiscolins as G protein-biased delta-opioid receptor agonists, and in vivo studies have demonstrated that they exert several beneficial effects via the central nervous system. The most unique and attractive advantage of rubiscolin-6 over other oligopeptides is its oral availability. Therefore, it can be considered a promising candidate for the development of a novel and safe drug. In this review, we show the therapeutic potential of rubiscolin-6, mainly focusing on its effects when orally administered based on available evidence. Additionally, we present a hypothesis for the pharmacokinetics of rubiscolin-6, focusing on its absorption in the intestinal tract and ability to cross the blood–brain barrier. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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16 pages, 1581 KiB

Open AccessReview

A Closer Look at Opioid-Induced Adrenal Insufficiency: A Narrative Review

by Flaminia Coluzzi, Jo Ann K. LeQuang, Salvatore Sciacchitano, Maria Sole Scerpa, Monica Rocco and Joseph Pergolizzi

Int. J. Mol. Sci. 2023, 24(5), 4575; https://doi.org/10.3390/ijms24054575 - 26 Feb 2023

Cited by 5 | Viewed by 5728

Abstract

Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors [...] Read more.

Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors for OIAI are not well known. OIAI can be diagnosed by a variety of tests, such as the morning cortisol test, but cutoff values are not well established and it is estimated that only about 10% of patients with OIAI will ever be properly diagnosed. This may be dangerous, as OIAI can lead to a potentially life-threatening adrenal crisis. OIAI can be treated and for patients who must continue opioid therapy, it can be clinically managed. OIAI resolves with opioid cessation. Better guidance for diagnosis and treatment is urgently needed, particularly in light of the fact that 5% of the United States population has a prescription for chronic opioid therapy. Full article

(This article belongs to the Special Issue Recent Progress of Opioid Research)

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