Identification of TGFß signatures in six murine models mimicking different osteoarthritis clinical phenotypes.

OBJECTIVE: TGFß is a key player in cartilage homeostasis and OA pathology. However, few data are available on the role of TGFß signalling in the different OA phenotypes. Here, we analysed the TGFß pathway by transcriptomic analysis in six mouse models of OA. METHOD: We have brought together seven expert laboratories in OA pathophysiology and, used inter-laboratories standard operating procedures and quality controls to increase experimental reproducibility and decrease bias. As none of the available OA models covers the complexity and heterogeneity of the human disease, we used six different murine models of knee OA: from post-traumatic/mechanical models (meniscectomy (MNX), MNX and hypergravity (HG-MNX), MNX and high fat diet (HF-MNX), MNX and seipin knock-out (SP-MNX)) to aging-related OA and inflammatory OA (collagenase-induced OA (CIOA)). Four controls (MNX-sham, young, SP-sham, CIOA-sham) were added. OsteoArthritis Research Society International (OARSI)-based scoring of femoral condyles and ribonucleic acid (RNA) extraction from tibial plateau samples were done by single operators as well as the transcriptomic analysis of the TGFß family pathway by Custom TaqMan® Array Microfluidic Cards. RESULTS: The transcriptomic analysis revealed specific gene signatures in each of the six models; however, no gene was deregulated in all six OA models. Of interest, we found that the combinatorial Gdf5-Cd36-Ltbp4 signature might discriminate distinct subgroups of OA: Cd36 upregulation is a hallmark of MNX-related OA while Gdf5 and Ltbp4 upregulation is related to MNX-induced OA and CIOA. CONCLUSION: These findings stress the OA animal model heterogeneity and the need of caution when extrapolating results from one model to another.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: introduction, methodology and recommendation overview.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The objective was to develop the first Canadian clinical practice guidelines for the management of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The guidelines were developed in accordance with the Appraisal of Guidelines for Research and Evaluation II tool. A Steering Committee and Working Group reviewed the relevant evidence on neuropathic pain management (encompassing screening and diagnosis, treatment and models of care) after SCI. The quality of evidence was scored using Grading of Recommendations Assessment, Development and Evaluation (GRADE). A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: The Working Group developed 12 recommendations for screening and diagnosis, 12 recommendations for treatment and 5 recommendations for models of care. Important clinical considerations accompany each recommendation. CONCLUSIONS: The Working Group recommendations for the management of neuropathic pain after SCI should be used to inform practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: Recommendations for treatment.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for treatment of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed the evidence for different treatment options and achieved consensus. The Working Group then developed clinical considerations for each recommendation. Recommendations for research are also included. RESULTS: Twelve recommendations were developed for the management of neuropathic pain after SCI. The recommendations address both pharmacologic and nonpharmacologic treatment modalities. CONCLUSIONS: An expert Working Group developed recommendations for the treatment of neuropathic pain after SCI that should be used to inform practice.

The CanPain SCI Clinical Practice Guideline for Rehabilitation Management of Neuropathic Pain after Spinal Cord: recommendations for model systems of care.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The project objectives were to develop the first Canadian recommendations on a model of care for the management of at- and below-level neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: On the basis of a review of the Accreditation Canada standards, the Steering Committee developed questions to guide the CanPainSCI Working Group when developing the recommendations. The Working Group agreed on recommendations through a consensus process. RESULTS: The Working Group developed five recommendations for the organization of neuropathic pain rehabilitation care in people with SCI. CONCLUSIONS: The Working Group recommendations for a model of care for at- and below-level neuropathic pain after SCI should be used to inform clinical practice.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: screening and diagnosis recommendations.

STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: To develop the first Canadian clinical practice guidelines for screening and diagnosis of neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. METHODS: The CanPainSCI Working Group reviewed evidence to address clinical questions regarding screening and diagnosis of neuropathic pain after SCI. A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: Twelve recommendations, based on expert consensus, were developed for the screening and diagnosis of neuropathic pain after SCI. The recommendations address methods for assessment, documentation tools, team member accountability, frequency of screening and considerations for diagnostic investigation. Important clinical considerations accompany each recommendation. CONCLUSIONS: The expert Working Group developed recommendations for the screening and diagnosis of neuropathic pain after SCI that should be used to inform practice.

Association between adiponectin and cartilage degradation in human osteoarthritis.

OBJECTIVE: Conflicting findings raise questions about the role of adiponectin in osteoarthritis (OA). The current study aimed to investigate in OA patients the association between the production of adiponectin and the grade of cartilage destruction, and to provide functional evidence for a potential role of adiponectin in OA. DESIGN: The expression of adiponectin was examined by immunohistochemistry in cartilage obtained from healthy individuals (n = 2; ages 56 and 41 years; 1 male and 1 female) and OA patients (n = 11; ages 64-79 years; 2 male and 9 female). The association between its production in chondrocytes and the grade of cartilage destruction was established on full-depth cartilage biopsies. The functional activity of adiponectin in OA cartilage was determined from the relation between the expression of adiponectin, its receptor, cartilage-specific components and factors involved in matrix degradation, and from the chondrocyte response to the full-length or the globular form of adiponectin. RESULTS: Adiponectin was not detected in healthy cartilage. Conversely, the adipokine was up-regulated in damaged tissue, but no strong association with the grade of cartilage destruction was found. We showed a positive correlation between adiponectin and mPGES or MMP-13 while AdipoR1 was related to the expression of type 2 collagen, aggrecan and Sox9. The full-length form of adiponectin but not the globular isoform, stimulated the production of PGE2 and MMP-13 activity in cultured human chondrocytes. CONCLUSIONS: The elevated level of adiponectin found in chondrocytes from OA patients might contribute to matrix remodelling during OA, the full-length isoform being the single active form.

Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the middle East region.

Neuropathic pain (NeP) has been the focus of extensive basic and clinical research over the past 20 years. This has led to an increased understanding of underlying pathophysiological mechanisms and the development of new therapeutic agents, as well as a clearer definition of the role of established medications. To date there are no published treatment guidelines for NeP in the Middle East. A multidisciplinary panel of Middle East and international experts met to review critically and reach a consensus on how best to apply evidence-based guidelines for the treatment of NeP (mainly peripheral NeP) in the Middle East. The expert panel recommended pregabalin, gabapentin and secondary amine tricyclic antidepressants (nortriptyline and desipramine) as first-line treatments for peripheral NeP. Serotonin-norepinephrine reuptake inhibitor antidepressants, tramadol and controlled-release opioid analgesics were recommended as second-line treatments. There is a need to increase diagnostic awareness of NeP, use validated screening questionnaires and undertake more treatment research in the Middle East region.

A survey of prelicensure pain curricula in health science faculties in Canadian universities.

OBJECTIVE: The present exploratory, descriptive study aimed to determine the designated time for mandatory pain content in curricula of major Canadian universities for students in health science and veterinary programs before being licensed. METHOD: Major Canadian university sites (n=10) were chosen where health science faculties included at least medicine (n=10) and nursing (n=10); many also included dentistry (n=8), pharmacy (n=7), physical therapy (n=8) and/or occupational therapy (n=6). These disciplines provide the largest number of students entering the workforce but are not the only ones contributing to the health professional team. Veterinary programs (n=4) were also surveyed as a comparison. The Pain Education Survey, developed from previous research and piloted, was used to determine total mandatory pain hours. RESULTS: The majority of health science programs (67.5%) were unable to specify designated hours for pain. Only 32.5% respondents could identify specific hours allotted for pain course content and/or additional clinical conferences. The average total time per discipline across all years varied from 13 h to 41 h (range 0 h to 109 h). All veterinary respondents identified mandatory designated pain content time (mean 87 h, range 27 h to 200 h). The proportion allotted to the eight content categories varied, but time was least for pain misbeliefs, assessment and monitoring/follow-up planning. CONCLUSIONS: Only one-third of the present sample could identify time designated for teaching mandatory pain content. Two-thirds reported 'integrated' content that was not quantifiable or able to be determined, which may suggest it is not a priority at that site. Many expressed a need for pain-related curriculum resources.

Effects of a semiochemical on feed conversion index and related indicators on fast-growing broilers housed during forty-two days.

Consequences of stress in poultry may be assessed through a wide range of parameters. A semiochemical named mother hen uropygial secretion analogue (MHUSA) is known to decrease stress in broilers. Because stress influences their feeding behavior, this trial has been built so as to test the influence of MHUSA on feed conversion index and related indicators. Two hundred forty chicks were placed into 24 similar crates (10 chicks per crate) at 1 d of age. After 35 d, chickens under MHUSA presented similar feed conversion index compared with control. A treatment effect was observed on both heterophil:lymphocyte ratio and corticosterone (MHUSA

Evidence for species differences in the regulation of MMPs by all-trans retinoic acid in cytokine-stimulated chondrocytes.

In inflammatory conditions, chondrocytes produce large amounts of matrix metalloproteases (MMP) and nitric oxide (NO) thought to contribute to joint degradation. We tested the ability of all-trans retinoic acid (ATRA, a retinoic acid receptor (RAR) agonist) to modulate these inflammatory genes in chondrocytes from humans or rats, chosen as representative of animal models of arthritis. All RAR subtypes and RXR-alpha or -beta were expressed at the mRNA level in both species, although IL-1beta (10 ng/ml) inhibited RAR subtypes more markedly in rat than in human cells. ATRA (300 or 1000 nM) inhibited IL-1-induced expression of iNOS and nitrites level in both species, although the NO pathway was induced maximally in rat cells. ATRA displayed controversial effects on MMPs between rat and human chondrocytes, especially for MMP-9 expression. The effects of ATRA were irrelevant to the nuclear translocation of AP-1. The present data underlines that retinoids have a species-dependent impact on IL-1-induced responses in chondrocytes, suggesting that extrapolation of their pharmacological properties from animal cells has a poor relevance to clinical situation.

Conversion from standard opioid therapy to once-daily oral extended-release hydromorphone in patients with chronic cancer pain.

This open-label, multicenter study assessed the efficacy and tolerability of conversion to once-daily OROS hydromorphone from previous opioid agonist therapy in patients with chronic cancer pain. Patients were stabilized on their previous therapy before conversion at a 5:1 ratio of morphine sulfate to hydromorphone hydrochloride. The OROS hydromorphone dose was titrated over 3 - 21 days to achieve effective analgesia and was maintained for up to 14 days. Efficacy was assessed using the Brief Pain Inventory (BPI). Adverse events and vital signs were monitored. Dose stabilization was achieved in 119 of the 127 (94%) patients who received the study medication; in 77%, stabilization was achieved with no titration steps. Mean BPI pain intensity ratings and BPI pain interference scores decreased significantly after OROS hydromorphone treatment compared with pretreatment values. Mean pain-relief level remained stable after conversion and throughout treatment with OROS hydromorphone. Adverse events were as expected for cancer patients receiving opioid agonists. There were no clinically significant changes in vital signs.

Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society.

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

[Medical certificates: law, deontology and practice]. / Des certificats médicaux: loi, déontologie et pratique.

At the start of the 21st century, in a society that gives the impression of switching century every five years because of its never-ending evolution, the general practitioner is confronted every day to more complex situations, including problems encountered at the legal level. These last few years, the legal interrogations relevant to medicine and its progress became considerably more extensive in Belgium, as in many other countries. The medical law and its regulation are the subject of many front titles in the press and of animated political debates. The main issues concern the organ transplantation, the meddling with human genetics, the questions related to the reproduction, euthanasia or the protection of the patient's rights. All these legal problems, without exception, are the subject of a great deal of attention in society and create to many controversies. The growing number of regulations in many fields of medicine, as well as their growing complexity, reinforces the importance of the medical law as a distinct discipline of legal sciences. More and more, the doctors of any qualification are required to guarantee, by adequate certificates, the health, the aptitude, the situation of disease of their patients. The patients can then have certain advantages granted by society. Out of concern for their patients, the experts are sometimes tempted not to be perfectly objective. This attitude can lead to penal or disciplinary sanctions and may undermine the confidence of people who exercise authority to give the requested advantages. The initial mistrust, which led to the system of the certificate, extends to those who were supposed to fully collaborate. How to leave this infernal round that sterilizes, denatures the medical act? While waiting for men of goodwill to consider the system and reform it, it remains with the writers of certificates to avoid the traps lying in their path. The purpose of this work is to propose models of certificate that experts can fill in accordance of the circumstances. It is only a guide and consequently, it sometimes requires an interpretation. This is why each model is described together with its justification and its traps.

Review article: moving towards common therapeutic goals in Crohn's disease and rheumatoid arthritis.

BACKGROUND: Crohn's disease (CD) and rheumatoid arthritis are chronic, progressive and disabling conditions that frequently lead to structural tissue damage. Based on strategies originally developed for rheumatoid arthritis, the treatment goal for CD has recently moved from exclusively controlling symptoms to both clinical remission and complete mucosal healing (deep remission), with the final aim of preventing bowel damage and disability. AIM: To review the similarities and differences in treatment goals between CD and rheumatoid arthritis. METHODS: This review examined manuscripts from 1982 to 2016 that discussed and/or proposed therapeutic goals with their supportive evidence in CD and rheumatoid arthritis. RESULTS: Proposed therapeutic strategies to improve outcomes in both rheumatoid arthritis and CD include: (i) evaluation of musculoskeletal or organ damage and disability, (ii) tight control, (iii) treat-to-target, (iv) early intervention and (v) disease modification. In contrast to rheumatoid arthritis, there is a paucity of disease-modification trials in CD. CONCLUSIONS: Novel therapeutic strategies in CD based on tight control of objective signs of inflammation are expected to change disease course and patients' lives by halting progression or, ideally, preventing the occurrence of bowel damage. Most of these strategies require validation in prospective studies, whereas several disease-modification trials have addressed these issues in rheumatoid arthritis over the last decade. The recent approval of new drugs in CD such as vedolizumab and ustekinumab should facilitate initiation of disease-modification trials in CD in the near future.

Pain expectations in neuropathic pain: Is it best to be optimistic?

BACKGROUND: Pain expectancy may be an important variable that has been found to influence the effectiveness of treatments for pain. Much of the literature supports a self-fulfilment perspective where expectations for pain relief predict the actual pain experienced. However, in conditions such as neuropathic pain (NeP) where pain relief is difficult to attain, expectations for pain relief could be unrealistic. The objective of this study was to investigate the relationship between realistic/unrealistic expectations and 6-month, post-treatment outcomes. METHODS: We performed a retrospective analysis of a large cohort of patients with NeP (n = 789) attending tertiary care centres to determine the association between unrealistic (both positive and negative) and realistic expectations with outcomes after multidisciplinary treatment. An expectation variable with three categories was calculated: realistic expectations were those whose expected reduction in pain was similar to the observed mean group reduction in pain, while optimistic and pessimistic expectations were those who over- or under-estimated the expected response to treatment, respectively. The association between baseline realistic/unrealistic expectations and 6-month pain-related disability, catastrophizing and psychological distress was assessed. RESULTS: Univariable analyses suggested that realistic expectations were associated with lower levels of disability, catastrophizing and psychological distress, compared to unrealistic expectations. However, after adjustment for baseline symptom severity, multivariable analysis revealed that patients with optimistic expectations had lower levels of disability, than those with realistic expectations. Those with pessimistic expectations had higher levels of catastrophizing and psychological distress at follow-up. CONCLUSIONS: These findings are largely congruent with the self-fulfilment perspective to expectations. SIGNIFICANCE: This study defined realistic pain expectations with patient data. Examining the relationship between expectations between pain and disability in a large cohort of patients with neuropathic pain.

Induction of UGT1A6 isoform by inflammatory conditions in rat astrocytes.

Alteration of drug metabolism under diseased conditions is of clinical importance. We have investigated the effects of inflammatory conditions on phase II drug-metabolizing enzyme activity in rat cultured astrocytes. Lipopolysaccharide (LPS) treatment was used to promote inflammatory conditions. Thus, we reported that LPS initiates an inflammatory response, which is mediated by pro-inflammatory mediators and free radical generation. An increase in astrocyte glucuronidation activity was observed after a 48-h LPS treatment. This increase in glucuronidation activity was associated with an up-regulation of the UGT1A6 isoform mRNA level as shown by RT-PCR and gene reporter assay. Moreover, this endotoxin-induced increase in UGT1A6 expression level was blocked by actinomycin D and cycloheximide, indicating the requirement for RNA and protein synthesis. The UGT1A6 expression enhancement could be prevented by anti-inflammatory drugs (dexamethasone and NS398) or nitric oxide synthase inhibitors (L-NAME and L-NMMA). Moreover, gel shift assay revealed increased activator protein-1 (AP-1) binding activity after LPS treatment. We propose, based on the data presented, that the action of LPS to induce UGT1A6 isoform up-regulation may be mediated by pro-inflammatory mediator accumulation, and AP-1 binding activity increase.

Methadone in the management of intractable neuropathic noncancer pain.

OBJECTIVE: To evaluate the role of methadone in the management of intractable neuropathic noncancer pain. METHODS: A case series of 50 consecutive noncancer pain patients who were seen at a tertiary care centre and treated with oral methadone for a variety of intractable neuropathic pain states. RESULTS: The mean age was 52.7 years and the mean duration of follow-up was 13.9 months. Post-discectomy nerve root fibrosis, complex regional pain syndrome, peripheral neuropathy and central spinal cord pain syndromes were the most common diagnoses. Over 90% had been treated with one or more tricyclic antidepressants and anticonvulsants and a similar number had received other adjuvant analgesics. All patients had failed treatment with one or more conventional opioid analgesics (mean 2.8) at a mean maximal morphine dose of 384 mg (or equivalents) per day. Twelve patients had failed spinal cord stimulation. Nineteen patients (38%) did not tolerate initial methadone titration or thought their pain was worse on methadone. Five patients (10%) declared initial benefit but required repetitive dose escalation and eventually became non-responders. Twenty-six patients (52%) reported mild (4), moderate (15), marked (6) or complete (1) pain relief and continued on methadone at a mean maintenance dose of 159.8 mg/day for a mean duration of 21.3 months. Fourteen patients (28%) reported improved function on methadone relative to previous treatments. CONCLUSIONS: Methadone appears to have unique properties including N-methyl-D-aspartate antagonist activity that may make it especially useful in the management of intractable neuropathic pain. This observation needs to be tested in randomized, controlled trials.

Neuropathic pain in a primary care electronic health record database.

BACKGROUND: Neuropathic pain (NP) is common in the adult population but is difficult to study in electronic health record (EHR) databases because it is a symptom rather than a pathologic diagnosis. The first step in studying NP in EHR databases is to develop methods for identifying patients with NP. The objectives of this study were to develop estimates of the prevalence of NP among patients in a primary care EHR database and describe these patients' demographic characteristics and health-care utilization. METHODS: This was a retrospective cohort study of de-identified data from a 5-year period (2005-2010) from 23 general practitioners (GPs) in 10 primary care practices in southwestern Ontario, Canada. International Classification of Diseases version 9 (ICD-9) diagnostic codes and medication prescriptions were used to identify patients with certain and probable NP. RESULTS: Different methods produced prevalence estimates ranging from 1.5% (for certain NP in the epidemiologically rigorous period cohort) to 11.2% (for certain NP + probable NP in the more inclusive database cohort). Patients in the NP groups had more GP visits, specialist referrals and analgesic prescriptions than patients without NP. CONCLUSION: This study represents a step towards being able to utilize EHR databases to study NP by proposing methods to identify patients with certain and probable NP in a primary care EHR database. Validation against a gold standard is the next step.

Impact on health-related quality of life and costs of managing chronic neuropathic pain in academic pain centres: Results from a one-year prospective observational Canadian study.

BACKGROUND: The management of chronic pain, including neuropathic pain (NeP), is a major public health issue. However, there is a paucity of data evaluating pain management strategies in real-life settings. OBJECTIVE: To inform policy makers about the economic value of managing chronic NeP in academic centres by conducting a subeconomic assessment of a Canadian multicentre cohort study aimed at determining the long-term outcomes of the management of chronic NeP in academic pain centres. Specific questions regarding the economic value of this type of program were answered by a subset of patients to provide further information to policy makers. METHODS: Baseline demographic information and several pain-related measurements were collected at baseline, three, six and 12 months in the main study. A resource use questionnaire aimed at determining NeP-related costs and the EuroQoL-5 Dimension were collected in the subset study from consenting patients. Statistical analyses were conducted to compare outcomes over time and according to responder status. RESULTS: A total of 298 patients were evaluated in the present economic evaluation. The mean (± SD) age of the participants was 53.7±14.0 years, and 56% were female. At intake, the mean duration of NeP was >5 years. Statistically significant improvements in all pain and health-related quality of life outcomes were observed between the baseline and one-year visits. Use decreased over time for many health care resources (eg, visits to the emergency room decreased by one-half), which resulted in overall cost savings. CONCLUSION: The results suggest that increased access to academic pain centres should be facilitated in Canada.

Sublingual absorption of selected opioid analgesics.

Ongoing interest in the improvement of pain management with opioid analgesics had led to the investigation of sublingual opioid absorption. The present report determined the percent absorption of selected opioid analgesics from the oral cavity of normal subjects under conditions of controlled pH and swallowing when a 1.0 ml aliquot of the test drug was placed under the tongue for a 10-minute period. Compared with morphine sulfate at pH 6.5 (18% absorption), buprenorphine (55%), fentanyl (51%), and methadone (34%) were absorbed to a significantly greater extent (p less than 0.05), whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not. Overall, lipophilic drugs were better absorbed than were hydrophilic drugs. Plasma morphine concentration-time profiles indicate that the apparent sublingual bioavailability of morphine is only 9.0% +/- 11.9% (SD) of that after intramuscular administration. In the same subjects the estimated sublingual absorption was 22.4% +/- 9.2% (SD), indicating that the sublingual absorption method may overestimate apparent bioavailability. When the oral cavity was buffered to pH 8.5, methadone absorption was increased to 75%. Thus, an alkaline pH microenvironment that favors the unionized fraction of opioids increased sublingual drug absorption. Although absorption was found to be independent of drug concentration, it was contact time dependent for methadone and fentanyl but not for buprenorphine. These results indicate that although the sublingual absorption and apparent sublingual bioavailability of morphine are poor, the sublingual absorption of methadone, fentanyl, and buprenorphine under controlled conditions is relatively high.