The good, the bad and the ugly of pain in haemophilia: Recent evidence on the epidemiology, molecular mechanisms and knowledge gaps preventing optimal treatment.

INTRODUCTION: Haemophilia is an inherited, X-linked blood clotting disorder caused by the deficiency of coagulation factors VIII (FVIII, haemophilia A) or IX (FIX, haemophilia B). Spontaneous bleeds are common in severe forms of haemophilia and can also occur in moderate and mild haemophilia. Severe or repeated bleeding at a joint can evolve into chronic haemophilic arthropathy, with functional damage of the joint, disability, and intense chronic articular pain. Nonetheless, acute and chronic pain may emerge due to secondary conditions related to bleedings. AIM: This narrative review aims to critically discuss the most recent evidence about pain in haemophilia to give healthcare professionals a clear picture of current knowledge hence favouring the optimisation of clinical management of pain. METHODS: Extensive literature search with the terms 'hemophilia' AND 'pain', focusing on the time window 2021-2023. RESULTS: Acute and chronic pain is a critical aspect of haemophilia at all ages. It should be considered a multifaceted phenomenon, with a positive role as an early emergency signal of a clinical event (haemarthrosis), and numerous detrimental aspects linked to its burden that heavily affects the health-related quality of life, with psychological and social consequences. CONCLUSION: Despite its prevalence and frequency in people with haemophilia, pain is often underestimated by healthcare professionals, leading to insufficient and inadequate treatment, also due to uncertainty linked to the presence of the coagulation disorder or arthritic flares.

Central sensitization mechanisms in chronic migraine with medication overuse headache: a study of thalamocortical activation and lateral cortical inhibition.

BACKGROUND: It is unclear whether cortical hyperexcitability in chronic migraine with medication overuse headache (CM-MOH) is due to increased thalamocortical drive or aberrant cortical inhibitory mechanisms. METHODS: Somatosensory evoked potentials (SSEP) were performed by electrical stimulation of the median nerve (M), ulnar nerve (U) and simultaneous stimulation of both nerves (MU) in 27 patients with CM-MOH and, for comparison, in 23 healthy volunteers (HVs) of a comparable age distribution. We calculated the degree of cortical lateral inhibition using the formula: 100 - [MU/(M + U) × 100] and the level of thalamocortical activation by analyzing the high frequency oscillations (HFOs) embedded in parietal N20 median SSEPs. RESULTS: Compared to HV, CM-MOH patients showed higher lateral inhibition (CM-MOH 52.2% ± 15.4 vs. HV 40.4% ± 13.3; p = 0.005), which positively correlated with monthly headache days, and greater amplitude of pre-synaptic HFOs (p = 0.010) but normal post-synaptic HFOs (p = 0.122). CONCLUSION: Our findings suggest that central neuronal circuits are highly sensitized in CM-MOH patients, at both thalamocortical and cortical levels. The observed changes could be due to the combination of dysfunctional central pain control mechanisms, hypersensitivity and hyperresponsiveness directly linked to the chronic intake of acute migraine drugs.

Perioperative hemorrhagic complications after laparoscopic sleeve gastrectomy: four-year experience of a bariatric center of excellence.

BACKGROUND: Bleeding and gastric fistula are the most common postoperative complications after laparoscopic sleeve gastrectomy (LSG). The long stapler line represents the most frequent source of bleeding, which ranges between 0 and 20%. The aim of this retrospective study was to analyze the 4-year experience of a high-volume center with respect to the prevention and management of perioperative LSG bleeding. METHODS: The prospectively maintained database from June 2012 to June 2016 was reviewed. Outcomes, especially perioperative bleeding (until patient discharge), its management, and follow-ups, were analyzed. RESULTS: Out of 870 LSG (603 females, 267 males), 31 cases (3.5%) of postoperative complications were registered: bleeding was the most frequent complication (1.9%). Hemoperitoneum was managed laparoscopically in 9/17 patients (52.9%) with only one conversion to laparotomy (11.1%). Conservative treatment successfully controlled bleeding in 8/17 patients (47.1%). However, four patients (50%) developed an infected hematoma; two of them were treated conservatively with a CT-guided drainage, and the other two were complicated by late gastric leak treated laparoscopically. No mortalities occurred in the investigated cases. CONCLUSIONS: In a high-volume center, the expected incidence of bleeding after LSG is 1.7% even after the adoption of all preventive strategies. The intraoperative protocol for detecting silent bleeding was effective, and no cases of bleeding were observed since its application. Our findings showed that the conservative management of postoperative bleeding should be considered as a high-risk condition for late leakage.

Management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day highly or moderately emetogenic chemotherapy: role of transdermal granisetron.

Granisetron transdermal delivery system (GTDS) is the first 5-HT3 drug to be transdermally delivered and represents a convenient alternative to oral and intravenous antiemetics for the treatment of chemotherapy-induced nausea and vomiting. GTDS is effective and well tolerated in patients receiving multiple-day moderate-to-highly emetogenic chemotherapy. In this setting noninferiority studies showed similar efficacy when GTDS was compared with intravenous and oral granisetron and intravenous palonosetron. GTDS has shown good cardiovascular safety; however, special caution is needed in patients at risk for developing excessive QTc interval prolongation and arrhythmias. So far, GTDS has been investigated for intravenous prevention in comparison with granisetron and palonosetron; however, further prospects open the route to future clinical investigations.

Implications of analgesics use in osteoporotic-related pain treatment: focus on opioids.

Bone loss is asymptomatic and will progress without pain and other symptoms until the occurrence of a fracture. The occurrence of a breaking bone induce acute pain determined and supported by a mechanical, inflammatory and neuropathic component. Very often the acute component evolves in a chronic musculoskeletal component. Overall objectives of the analgesic therapy can be summarized in pain relief, improving sleep, improve mobility, reduce anxiety, emotional component and depression. Osteoporosis is predominantly a condition of the elderly, more likely to have coexisting cardiovascular disease and age-related decline in renal function, receiving treatment for one or more comorbid conditions, taking multiple medications. Analgesic treatment with NSAIDs has negative effects on skeletal health and healing of the injured skeleton and increase risk of adverse events especially in older patients. Despite all opioids therapy represents a mainstay in the treatment of patients with moderate to severe pain, it can induce an endocrinopathy, which may affect bone metabolism. The negative effects of opioids on hormonal axis are not the same for all molecule and the choice of drug can be crucial in the treatment of patients with chronic pain.

Bone pain mechanism in osteoporosis: a narrative review.

Bone pain in elderly people dramatically affects their quality of life, with osteoporosis being the leading cause of skeletal related events. Peripheral and central mechanisms are involved in the pathogenesis of the nervous system sensitization. Osteoporosis in the elderly has been associated with increased density of bone sensory nerve fibers and their pathological modifications, together with an over-expression of nociceptors sensitized by the lowering pH due to the osteoclastic activity. The activation of N-methyl-D-aspartate (NMDA) receptors and the microglia, as a response to a range of pathological conditions, represent the leading cause of central sensitization. Unfortunately, osteoporosis is named the "silent thief" because it manifests with painful manifestation only when a fracture occurs. In the management of patients suffering from bone pain, both the nociceptive and the neuropathic component of chronic pain should be considered in the selection of the analgesic treatment.

A prospective evaluation on external jugular vein cut-down approach for TIVAD implantation.

BACKGROUND: Totally implantable venous access devices can be implanted both by percutaneous approaches and by surgical approaches with cephalic vein or external jugular vein cut-down techniques that are related to low intraoperative complication rates. The authors report a prospective evaluation of 83 consecutive external jugular vein cut-down approaches for totally implantable venous access devices implantation. METHODS: Eighty three consecutive patients (28 M, 55 F, mean age 54.2) suffering from solid tumors (58) or hematologic diseases (25) were consecutively submitted to totally implantable venous access devices insertion through external jugular vein cut-down approach (75 on right side, 8 on left side). RESULTS: All devices were surgically implanted; no instances of intraoperative complications were detected. After a minimum follow-up of 150 days, only one case of wound hematoma and one case of device malfunction due to incorrect catheter angulation were noted. Postoperative patient satisfaction was evaluated by the use of specific questionnaire that demonstrated a good satisfaction and compliance (92.8%) of patients with implanted devices. CONCLUSIONS: Despite the lack of controlled studies comparing external jugular vein cut-down approach vs other approaches, this approach should be considered as a tool for long-term central vein catheters positioning, both as an alternative and for primary approach.

Perioperative Pain Management in Hemophilic Patient Undergoing Orthopedic Surgery: A Narrative Review.

BACKGROUND: Hemophilia type A and B is associated with spontaneous bleeding in muscle tissues and joints. Acute hemarthrosis, representing 70-80% of all bleedings in severe hemophilia patients, is extremely painful. When surgical procedures are needed in hemophiliac patients, perioperative management should be planned with a multidisciplinary team. Our narrative review, through a rigorous analysis of the current literature, focuses on pain management in hemophiliac patients. METHODS: The report synthesizes a literature review on hemophilia, adapting PRISMA guidelines. It identifies a research question on surgical procedures and perioperative pain management. Various sources, including electronic databases, are utilized. Study inclusion criteria are defined based on the research question. Forty studies are included. A detailed study selection is illustrated. RESULTS: Guidelines for managing acute postoperative pain in the general population advocate for a multimodal analgesic administration to enhance synergistic benefits, reduce opioid requirements, and minimize side effects. Recent recommendations from the World Federation of Hemophilia (WFH) for postoperative pain management in hemophilia patients suggest tailoring treatment based on pain levels, in coordination with anesthesiologists. CONCLUSIONS: Pain management in hemophiliac patients undergoing orthopedic interventions requires a multidisciplinary approach, with further research needed to define a reliable global standard of treatment.

Neuropathic pain experience in symptomatic and presymptomatic subjects carrying a transthyretin gene mutation.

Introduction: Pain is a common symptom of hereditary transthyretin amyloidosis (ATTRv), however, its occurrence in late-onset ATTRv has not been investigated thoroughly. Our aim was to describe the pain experience and its impact on quality of life (QoL) in symptomatic patients and presymptomatic carriers harboring a transthyretin (TTR) gene mutation with a late-onset phenotype. Materials and methods: Study participants (aged ≥18 years) were consecutively recruited from four Italian centers. Clinical disability was assessed using the Familial Amyloid Polyneuropathy (FAP) stage and Neuropathy Impairment Score (NIS). The Norfolk questionnaire evaluated QoL and the Compound Autonomic Dysfunction Test assessed autonomic involvement. Neuropathic pain was screened using the Douleur Neuropathique 4 (DN4) questionnaire, and pain intensity and its impact on daily activity were assessed using the Brief Pain Inventory severity and interference subscores. Data on the type of TTR mutation, presence of cardiomyopathy, treatment, and Body Mass Index (BMI) were collected. Results: Overall, 102 subjects with TTR mutations (mean age ± SD 63.6 ± 13.5 years) were recruited, including 78 symptomatic patients (68.1 ± 10.9 years) and 24 presymptomatic carriers (49 ± 10.3 years). Pain was reported by 75.5% of all subjects, but was more frequent in symptomatic patients than in presymptomatic carriers (85.9 vs. 41.6%, respectively). Pain exhibited neuropathic features (DN4≥4) in 69.2% of symptomatic patients and in 8.3% of presymptomatic carriers. Subjects with neuropathic pain were older (p = 0.015) had worse FAP stage (p < 0.001), higher NIS scores (p < 0.001), greater autonomic involvement (p = 0.003), and a lower QoL (p < 0.001) than those without neuropathic pain. Neuropathic pain was associated with higher pain severity (p < 0.001) and had a significant negative impact on daily activities (p < 0.001) Neuropathic pain was not associated with gender, mutation type, TTR therapy, or BMI. Conclusion: Approximately 70% of late-onset ATTRv patients complained of neuropathic pain (DN4≥4) that worsened as peripheral neuropathy progressed and increasingly interfered with daily activities and QoL. Notably, 8% of presymptomatic carriers complained of neuropathic pain. These results suggest that assessment of neuropathic pain may be useful to monitor disease progression and identify early manifestations of ATTRv.

Improving assessment and management of pain in hemophilia: an Italian Delphi consensus statement.

Comprehensive evidence-based guidelines and well-validated assessment scales for pain in people with hemophilia (PwH) are needed. Here, we report 28 statements covering five topics on pain assessment and management in pediatric and adult PwH that were developed by 60 Italian hemophilia specialists during a Delphi consensus process. Overall, a clear consensus was achieved for 19 of the 28 statements. Consensus was reached on all statements on the topic of pain assessment and quality of life (QoL), including the need for regular pain assessment on a quantitative scale, the importance of distinguishing between different pain types, and the need to evaluate the impact of pain on patient QoL. The other four topics concerned acute and chronic pain management in adults and in children. Consensus was reached on statements regarding non-pharmacologic treatment and the use of first-line paracetamol (acetaminophen). There was a lack of consensus regarding the use of non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or opioids.

Possible role of 5-alpha reductase inhibitors in non-invasive bladder urothelial neoplasm: multicenter study.

BACKGROUND: About 75% of urothelial bladder cancers are non-muscle invasive (NMIBC), and limited to mucosa (Ta or CIS) or sub-mucosa (T1). An increase of androgen expression and androgen receptors has a positive effect on oncogenic expression. We aimed to evaluate whether 5-alpha reductase inhibitors (5-ARI) have a role in NMIBC. METHODS: We retrospectively evaluated the clinical and pathological data of 423 patients with NMIBC who underwent transurethral bladder resection. We considered the number of resections, number of total recurrences, time of recurrences, and histopathology details. The population was classified into two groups: treated and untreated with 5-ARIs. The enrolled patients were in treatment with 5ARIs for symptomatic prostatic hyperplasia for at least 12 months. Mean follow-up time was 30.43 months. RESULTS: Patients treated with 5-ARIs had a lower rate of recurrence (14%) than the untreated group (37%). There was a significant difference in the mean number of recurrences between the untreated and the treated group (P=0.006). Furthermore, the treated group showed a significantly greater number of low than high grade tumors, compared to the untreated group (P≤0.05). There was a significant decrease in the number of muscle invasive tumors in treated patients (P=0.032). The recurrence-free survival rate of patients treated with 5-ARIs was significantly higher (P=0.0001). CONCLUSIONS: Long-term treatment with 5-ARIs might reduce the risk of bladder tumor recurrence, extension of lesions and increase the recurrence-free survival rate. A long-term, randomized prospective study could definitively assess the possible role of these drugs.

Emerging therapies in metastatic bone pain.

INTRODUCTION: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain. AREAS COVERED: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the 'vicious cycle' of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors. EXPERT OPINION: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile.

Buprenorphine: Far Beyond the "Ceiling".

Chronic pain, including neuropathic pain, represents an untreated disease with important repercussions on the quality of life and huge costs on the national health system. It is well known that opioids are the most powerful analgesic drugs, but they represent the second or third line in neuropathic pain, that remain difficult to manage. Moreover, these drugs show several side effects that limit their use. In addition, opioids possess addictive properties that are associated with misuse and drug abuse. Among available opioids compounds, buprenorphine has been suggested advantageous for a series of clinical reasons, including the effectiveness in neuropathic pain. Some properties are partly explained by its unique pharmacological characteristics. However, questions on the dynamic profile remain to be answered. Pharmacokinetics optimization strategies, and additional potentialities, are still to be explored. In this paper, we attempt to conceptualize the potential undiscovered dynamic profile of buprenorphine.

An Italian Expert Consensus on the Use of Opioids for the Management of Chronic Non-Oncological Pain in Clinical Practice: Focus on Buprenorphine.

PURPOSE: The aim of the present work was to evaluate the knowledge and prescriptive habits of clinicians involved in the management of chronic non cancer pain (CNCP), with a special focus on the use of opioids. METHODS: A Delphi method was used. A Board of specialists elaborated and discussed a series of statements, based on available literature and personal clinical expertise, about particularly controversial topics on pain pathophysiology and treatment. A Panel of experts in the field of pain management, selected by the Board, was invited to vote the proposed statements, indicating the level of agreement on a 5-point Likert scale (1: strongly disagree; 2: disagree; 3: partially agree; 4: agree; 5: strongly agree). The threshold for consensus was set at minimum 66.6% of the number of respondents with a level of agreement ≥4 (Agree or Strongly agree). RESULTS: The Board included 5 pain therapists, 1 pharmacologist and 1 methodology expert and drew up a total of 36 statements (for a total of 40 requested answers)". A total of 100 clinicians were included in the Expert Panel. Respondents were 89 (89%). Consensus was achieved for 32 out of 40 answers. Most of the lack of consensus was recorded for statements regarding opioids use, and resulted from a low level of agreement (3 on the Likert scale), suggesting a neutral position deriving from a lack of knowledge rather than a strong contrary opinion. CONCLUSION: Most of the proposed items reached consensus, suggesting a generally homogeneous approach to CNCP management. However, the lack of consensus recorded for several items regarding opioid use confirms the need to fill important gaps in the knowledge of available agents. A clear explanation of the peculiar pharmacological properties of drugs associated with potential clinical advantages (such as buprenorphine) will help optimize pain treatment in both primary care and hospital settings and improving pain control in CNCP patients.

Pain assessment and management in Italian Haemophilia Centres.

BACKGROUND: Although the widespread use of factor VIII/IX replacement therapy has significantly reduced the severity of arthropathy in persons with haemophilia (PWH), some develop degenerative joint changes, associated with significant pain. The aim of this survey was to investigate the management and perception of pain among Italian physicians who treat PWH. MATERIALS AND METHODS: Between September and October 2017, a questionnaire was distributed to 35 Italian haemophilia treatment centres (60 physicians). RESULTS: Fifty-three haemophilia specialists completed the survey. We found that there was good agreement (98.1%) on the need to investigate pain at each clinical visit, but there was heterogeneity in the opinions of haemophilia specialists with regards to the availability of validated guidelines (35.8%) and whether pain specialists should be a part of the comprehensive care team in daily clinical practice (58.5%). Haemophilia specialists also agreed pain should be evaluated using a rating scale validated in PWH (88.7%). Pain was mainly managed by the haemophilia specialists themselves, supported by a physiatrist and physiotherapist, while a pain specialist was only involved in 26.4% of cases. The combination of paracetamol with tramadol or codeine was the most common first-line treatment, while cyclo-oxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs, and opioids were less commonly used. DISCUSSION: There are some unmet needs in Italy regarding pain management for PWH and the management of pain in these patients by haemophilia specialists. There is a lack of evidence-based guidelines for these specialists to use, as well as a reluctance to involve pain specialists. The lack of spontaneous reporting of pain by PWH, despite using pain relief, highlights the need for clinicians to actively ask patients about any pain they may be experiencing.

Efficacy and safety of fentanyl HCl iontophoretic transdermal system compared with morphine intravenous patient-controlled analgesia for postoperative pain management for patient subgroups.

BACKGROUND AND OBJECTIVE: Inadequate postoperative pain control remains a problem for many patients undergoing surgery. This study presents subgroup analyses from a large, randomized, multicentre, European study comparing the efficacy and safety of the fentanyl HCl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia for postoperative pain management. METHODS: The efficacy and safety of the fentanyl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia were evaluated for patients divided by surgery type, sex, American Society of Anesthesiologists physical status and type of anaesthesia used during surgery. Efficacy measures included a patient global assessment of the method of pain control (a rating of 'good' or 'excellent' was considered as a success rating) and mean last pain intensity scores in the first 24 h. Discontinuation rates and the incidence of adverse events were also evaluated. RESULTS: Numerically similar percentages of patients in most subgroups reported success on the last patient global assessment in the first 24 h for both the fentanyl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia. Similar percentages of investigators reported success ratings on the investigator global assessment at the last assessment for both treatment groups regardless of surgery type, except for the knee surgery subgroup (fentanyl iontophoretic transdermal system, 75%; morphine intravenous patient-controlled analgesia, 95%). Mean last pain intensity scores in the first 24 h after surgery were similar in all subgroups. Rates of patient withdrawals and the incidence of adverse events were generally similar between treatment groups in the patient subgroups. CONCLUSION: The fentanyl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia are comparably well tolerated and effective methods of pain control, regardless of sex, American Society of Anesthesiologists physical status or the type of anaesthesia used for surgery, and following most surgery types.

Direct-acting antivirals improve endothelial function in patients with chronic hepatitis: a prospective cohort study.

Hepatitis C virus (HCV) infection is associated with increased cardiovascular risk. We evaluated effects of direct-acting antiviral agents (DAAs) on flow-mediated dilation (FMD), a recognized marker of cardiovascular risk. We evaluated FMD and post-ischemic hyperemia (PIH) in consecutive HCV out-patients before starting DAAs, at the end of treatment (Teot) and 12 weeks thereafter. In 22 HCV subjects (age 64.0 years), baseline FMD was 4.52% ± 1.90 and PIH of 5814.4 (IQR 3786.9-7861.9). At (Teot), all patients showed undetectable levels of HCV-RNA and FMD changed from 4.52% ± 1.90 to 9.39% ± 4.06 (p < 0.001), with a direct correlation between changes in FMD and baseline HCV-RNA levels (r = 0.494, p = 0.020). In parallel, PIH increased from 5814.4 (IQR 3786.9-7861.9) to 7277.6 (IQR 4579.8-10388.8) (p = 0.019). Twelve weeks after Teot, all patients had persistently negative HCV-RNA, FMD was 10.9% ± 4.65 and PIH was 10930.3 (IQR 6254.6-18248.2) suggesting a further significant improvement in these parameters. Results remained significant regardless of the presence of cardiovascular risk factors, whereas FMD changes were not statistically significant in subjects with cirrhosis. A persistent and significant improvement in endothelial function is observed in HCV patients obtaining viral eradication with DAAs treatment. This might suggest a beneficial effect of DAAs treatment on cardiovascular risk profile of HCV patients.

Indantadol, a novel NMDA antagonist and nonselective MAO inhibitor for the potential treatment of neuropathic pain.

Indantadol is an oral and nonselective monoamine oxidase inhibitor and NMDA antagonist that is being developed by Vernalis plc, under license from Chiesi Farmaceutici SpA, for the potential treatment of neuropathic pain. In preclinical studies, indantadol exhibited neuroprotective effects after kainite-induced seizures, and displayed anticonvulsant and antihyperalgesic activity. Indantadol also caused a dose-dependent decrease in exploratory motility. In a human heat-capsaicin-induced pain model, indantadol at a dose of 500 mg effectively reduced the area of secondary hyperalgesia to 67%. Indantadol undergoes extensive liver metabolism, withthe formation of two major metabolites - CHF-3567 and 2-aminoindane. The drug is excreted in urine partially as the parent compound, but mostly as CHF-3567. The tolerability profile of indantadol at single doses up to 600 mg and twice-daily doses up to 400 mg in clinical trials was significantly more favorable than for other NMDA antagonists. Most side effects have been observed to be mild, and include dizziness and asthenia. Indantadol is currently in phase II clinical trials in patients with diabetic peripheral neuropathic pain. Given the results available to date, indantadol may have a role in the treatment of neuropathic pain if the favorable pharmacokinetic profile and efficacy of the drug are maintained in more extensive clinical trials.

Good clinical practice guide for opioids in pain management: the three Ts - titration (trial), tweaking (tailoring), transition (tapering).

BACKGROUND AND OBJECTIVES: Achieving good clinical practice in the use of opioids as part of a comprehensive pain management regimen can face significant challenges. Despite guidelines from governmental and pain society/organization sources, there are still significant hurdles. A review of some basic tenets of opioid analgesia based on current published knowledge and experiences about this important healthcare imperative is warranted. CONTENT: Consistent with guidelines, the literature supports using the lowest total opioid dose that provides adequate pain control with the fewest adverse effects. Titration (or trial) during opioid initiation is a way of starting low and going slow (and assessing the appropriateness of a specific opioid and formulation). Recognizing that multiple factors contribute to an individual's personal experience of pain, the physical, psychological, social, cultural, spiritual, pharmacogenomic, and behavioral factors of the individual patient should be taken into account (tweaking, or tailoring). Finally, for those patients for whom transition (tapering) from opioid is desired, doing so too rapidly can have negative consequences and minimization of problems during this step can be achieved by proper tapering. CONCLUSION: We conclude that a simultaneously aggressive, yet conservative, approach is advocated in the literature in which opioid therapy is divided into three key steps (the 3 T's): titration (or trial), tweaking (or tailoring), and transition (or tapering). Establishment of the 3 T's along with the application of other appropriate good medical practice and clinical experience/judgment, including non-pharmacologic approaches, can assist healthcare providers in the effort to achieve optimal management of pain.