Treatment Of Chronic Pain Conditions Research Articles

Transforming personalized chronic pain management with artificial intelligence: A commentary on the current landscape and future directions

Artificial intelligence (AI) has the potential to revolutionize chronic pain management by guiding the development of effective treatment strategies that are tailored to individual patient needs. This potential comes from AI's ability to analyze large and heterogeneous datasets to identify hidden patterns. When applied to clinical datasets of a particular patient population, AI can be used to identify pain subtypes among patients, predict treatment responses, and guide the clinical decision-making process. However, integrating AI into the clinical practice requires overcoming challenges such as data quality, the complexity of human pain physiology, and validation against diverse patient populations. Targeted, collaborative efforts among clinicians, researchers, and AI specialists will be needed to maximize AI's capabilities and advance current management and treatment of chronic pain conditions.

Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models.

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid-conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.

Spinal cord stimulation has a place in the treatment of chronic pain conditions.

Spinal cord stimulation has a place in the treatment of chronic pain conditions.

Transcutaneous auricular vagus nerve stimulation for the treatment of myoarthropatic symptoms in patients with craniomandibular dysfunction – a protocol for a randomized and controlled pilot trial

BackgroundTemporomandibular disorders (TMD) are a collective term for pain and dysfunction of the masticatory muscles and the temporomandibular joints. The most common types of TMD are pain-related, which may impact the psychological behavior and quality of life. Currently, the most popular methods for the treatment of TMD patients are occlusal splint therapy, often in combination with physical- and/or pharmacotherapy. However, due to the complexity of etiology, the treatment of chronic TMD remains a challenge. Recently, CE-certified systems for non-invasive VNS (transcutaneous auricular vagus nerve stimulation, taVNS) have become available and show positive effects in the treatment of chronic pain conditions, like migraine or fibromyalgia, with which TMD shares similarities. Therefore, it is the main purpose of the study to evaluate the feasibility of daily taVNS against chronic TMD and to assess whether there is an improvement in pain severity, quality of life, and kinetic parameters.MethodsThis study is designed as a single-blinded, double-arm randomized controlled trial (RCT) in a 1:1 allocation ratio. Twenty adult patients with chronical TMD symptoms will be enrolled and randomized to stimulation or sham group. In the stimulation group, taVNS is performed on the left tragus (25 Hz, pulse width 250 µs, 28 s on/32 s off, 4 h/day). The sham group will receive no stimulation via a non-functional identical-looking electrode. Validated questionnaire data and clinical parameters will be collected at the beginning of the study and after 4 and 8 weeks. The compliance of a daily taVNS of patients with chronical TMD will be evaluated via a smartphone app recording daily stimulation time and average intensity. Additionally, the treatment impact on pain severity and quality of life will be assessed with different questionnaires, and the effect on the mandibular mobility and muscle activity will be analyzed.DiscussionThis is the first clinical trial to assess the feasibility of taVNS in patients with chronic TMD symptoms. If taVNS improves the symptoms of TMD, it will be a significant gain in quality of life for these chronic pain patients. The results of this pilot study will help to determine the feasibility of a large-scale RCT.Trial registrationThis study has been registered in the DRKS database (DRKS00029724).

Acute Precipitated Opioid Withdrawal With Akathisia, Delirium, and Lactic Acidosis from Low-Dose Naltrexone for Chronic Pain: Case Report

BACKGROUND: Low-dose naltrexone (LDN) is an increasingly popular medication to enhance analgesia and decrease opioid reliance in patients with chronic pain. CASE REPORT: We present the case of a 66-year-old man on long-term opioids for chronic pain who was initiated on 1 mg of LDN for enhanced analgesia and subsequently went into severe precipitated opioid withdrawal (POW), a reaction understood to be rare at such low doses. CONCLUSION: LDN has been introduced into pain medicine as a safe and effective adjunct for the treatment of chronic pain conditions in both opioid-naive patients and those on concomitant opioid therapy. While this is generally considered a safe practice, LDN initiation can cause acute precipitated withdrawal in certain individuals already on opioids, even at low doses previously thought to be free from this risk. We recommend pain providers consider this effect and be prepared to manage POW when prescribing LDN. KEY WORDS: Low-dose naltrexone, LDN, chronic pain, precipitated opioid withdrawal, case report

Investigating the effectiveness of oral ketamine on pain, mood and quality of life in treatment resistant chronic pain

IntroductionChronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic.MethodsThis study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale.Results73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine.DiscussionThis work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key messageThis real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions.

Tolperisone induces UPR-mediated tumor inhibition and synergizes with proteasome inhibitor and immunotherapy by targeting LSD1

ABSTRACT Background Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy. Research design and methods The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy. Results Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype. Conclusions Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.

Learning pain from others: a systematic review and meta-analysis of studies on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning.

Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that contribute to these effects could help in the development of strategies for optimizing treatment of chronic pain conditions. We systematically reviewed and meta-analyzed the literature on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning (OL). A systematic literature search was conducted in the databases PubMed, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus, and Academic Search Ultimate. Twenty-one studies were included in the systematic review, 17 of which were suitable for meta-analysis (18 experiments; n = 764 healthy individuals). The primary end point was the standardized mean difference (SMD) for pain following placebo cues associated during OL with low vs high pain. Observational learning had a small-to-medium effect on pain ratings (SMD 0.44; 95% confidence interval [CI] 0.21-0.68; P < 0.01) and a large effect on pain expectancy (SMD 1.11; 95% CI 0.49-2.04; P < 0.01). The type of observation (in-person vs videotaped) modulated the magnitude of placebo hypoalgesia/nocebo hyperalgesia (P < 0.01), whereas placebo type did not (P = 0.23). Finally, OL was more effective when observers' empathic concern (but no other empathy-related factors) was higher (r = 0.14; 95% CI 0.01-0.27; P = 0.03). Overall, the meta-analysis demonstrates that OL can shape placebo hypoalgesia and nocebo hyperalgesia. More research is needed to identify predictors of these effects and to study them in clinical populations. In the future, OL could be an important tool to help maximize placebo hypoalgesia in clinical settings.

Pill Counting as an Intervention to Enhance Compliance and Reduce Adverse Outcomes with Analgesics Prescribed for Chronic Pain Conditions: A Systematic Review.

Appropriate use of opioid analgesics is a key concern within the field of pain medicine. Several methods exist to discourage abuse and facilitate effective treatment regimens. Pill counting is often cited as one such method and frequently employed in varying fashions within clinical practice. However, to date, there is no published review of the evidence to support this practice. This was a comprehensive review of the available literature that was conducted with analysis of the efficacy and practical application of pill counting during treatment of chronic pain conditions. There is paucity in data regarding pill count importance in pain management. Pill count is a very important tool to monitor compliance of opioids use which in turn can prevent several complications associated with opioid misuse. Pill counting may be used in conjunction with other abuse deterrents, although increased support for this practice requires standardized methods of pill counting and further analysis of its effectiveness.

Online ACT intervention for fibromyalgia: An exploratory study of feasibility and preliminary effectiveness with smartphone-delivered experiential sampling assessment

IntroductionAcceptance and commitment therapy (ACT) is an effective treatment for chronic pain conditions. ACT seeks to produce clinical change by enhancing Psychological Flexibility (PF). This exploratory (feasibility and preliminary effectiveness) study presents a pilot application of an online ACT group intervention for fibromyalgia (FM) with an extensive Experiential Sampling (ES) assessment of outcome and process variables via smartphone. Method5-weekly ACT online group sessions were applied to 9 female FM patients. Questionnaire-based assessments of several clinical outcomes and PF processes were conducted pre- and post-intervention, and at 6-month follow-up. Extensive (6 weeks pre- and 6 weeks post-intervention) smartphone-delivered ES was implemented to gather process and outcome data in the patients' usual contexts. Clinically significant change was evaluated both at the group level and individually. ResultsThis treatment format appears to be feasible and acceptable to participants, with good adoption and completion rates (75 %) and excellent rates of treatment completion and clinical adherence (100 %). Participants showed significant reductions in affective pain, distress and biopsychosocial impact of FM both post-intervention and at 6-month follow-up (as measured with questionnaires), as well as significant improvements in satisfaction with actions and emotional discomfort (as measured through ES). Multilevel regression analyses indicated that PF-related processes assessed through ES had a significant impact on clinical outcomes and predicted the impact of FM at the 6-month follow-up. ConclusionsA brief online group ACT intervention for FM was both feasible and acceptable to participants. Also, there was preliminary evidence of effectiveness in enhancing pain-related PF and producing clinical benefits in FM.

NADPH Oxidases in Pain Processing.

Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.

A Look at Commonly Utilized Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) in Chronic Pain.

Chronic pain continues to be one of the leading healthcare cost burdens in the United States and is typically defined as ongoing pain, lasting longer than six months. Various treatment options exist for chronic pain, including physical therapy, medical management, pain psychology, and interventional therapies. Pain medications have been the mainstay of treatment for chronic pain conditions with an increasing use of membrane stabilizers and antidepressants to treat neuropathic pain conditions. Specifically, serotonin noradrenaline reuptake inhibitors (SNRIs) have been used to treat a range of pain conditions expanding from everyday use for depressive disorders. SNRIs, including duloxetine, venlafaxine, and milnacipran, have demonstrated efficacy in reducing pain in musculoskeletal pain (chronic low back pain and osteoarthritis), fibromyalgia, and neuropathic pain conditions (peripheral diabetic neuropathy). The article describes the function, role, and use of SNRIs to treat chronic and neuropathic pain by altering the noradrenergic descending inhibitory pathways.

The Role of Selective Adenosine Receptor Ligands on Inflammatory Pain

While pain is frequent manisfestation of several disease processes, chronic pain has been described as an established disorder with debilitating ramifications on health and lifestyle. The currently available analgesics for the treatment of chronic pain are often ineffective and accompanied by undesirable adverse effects, which invites for safer and more efficacious alternatives. Adenosine is a naturally‐occurring purinergic nucleoside that is involved in cell signaling in multiple tissue types. Although the activation of adenosine receptors can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A1, A2A, A2B and A3 receptors) are not fully understood. The aim of this work was to investigate the role played by different adenosine receptor ligands on inflammatory pain conditions. Inflammatory pain was induced by intra‐plantar injection of Complete Freund’s Adjuvant (CFA) into the left hindpaw of adult male Sprague Dawley rats. Von Frey filaments were applied to the mid‐plantar aspect of the left hind paw using the “up‐down” method to determine the CFA‐induced mechanical allodynia (expressed as paw withdrawal threshold, PWT). Neither the A2A selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A2B selective agonist BAY 60‐6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, both the A1 selective agonist (±)‐5′‐Chloro‐5′‐deoxy‐ENBA, and the A3 selective agonist 2‐Cl‐IB‐MECA produced a significant reversal of the PWT at the highest dose of 1 mg/kg, suggesting antinociceptive effects of the A1 and A3 adenosine receptors. Co‐administration of the selective antagonists of A1 and A3 receptors PSB36 (1 mg/ml) and MRS‐3777 (1 mg/ml); respectively, significantly reduced the anti‐nociceptive effects of both (±)‐5′‐Chloro‐5′‐deoxy‐ENBA, and 2‐Cl‐IB‐MECA (1 mg/kg) on PWT one hour post‐drug administration. Both the A2A selective antagonist ZM 241385 and the A2B selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. In conclusion, A1, A2A, A2B and A3 adenosine receptors are involved in mediating inflammatory pain states, and represent promising targets for the treatment of chronic pain conditions.

This Month in Anesthesiology

This Month in Anesthesiology

"The Pain Left, I Was Off and Running": A Qualitative Analysis of Group Acupuncture and Yoga Therapy for Chronic Pain in a Low-Income and Ethnically Diverse Population.

Introduction: Chronic pain and the current opioid epidemic are pressing public health concerns, especially in low-income and ethnically diverse communities. Nonpharmacologic therapies that are safe, effective, and acceptable for the treatment of chronic pain conditions may provide a solution for addressing this issue. This qualitative analysis explores the experience of study participants who received combined acupuncture and yoga therapy (YT) to treat chronic pain delivered in a primary care setting. Methods: The group acupuncture with yoga therapy for chronic neck, low back, and osteoarthritic pain trial (GAPYOGA) assessed the feasibility and effectiveness of group acupuncture (GA) combined with YT in a low-income, racial, and ethnically diverse population. Individual in-depth interviews were conducted with a subset of patients in the trial. Nineteen participants were interviewed for qualitative analysis of their experience. Using the immersion and crystallization method, transcribed interviews were analyzed for themes meaningfully representing participant experience. Results: The combined GA and YT resulted in significant pain relief and transformative healing experiences. Three themes emerged from participant narratives: (1) transformative engagement with self in the healing process through pain relief, psychological well-being, and self-efficacy; (2) therapeutic relationship with acupuncture and yoga providers; and (3) fostering relationships with fellow participants in the group. Discussion: In this study of a low-income and ethnically diverse population, the combination of acupuncture and YT was found to alleviate pain, improve function, promote psychological well-being, and engage participants in self-care practices in a transformative healing process-resulting in physical and psychological benefits.

Symposium

Prescription opioid misuse is widely rampant and increasing worldwide. Similar rising trends with reports of patients suffering from prescription opioid dependence are being reported from India. Unregulated prescription of opioids as pain-killers in the US contributed to onset of the ‘epidemic’ of prescription opioid misuse. Pain is a multidimensional and complex experience that has physical, social, spiritual and psychological aspects. Ensuring availability of opioids for treatment of chronic pain conditions is crucial. WHO estimates that 20 million people required end-of-life palliative care, of whom 78 % lived in low and middle income countries. India ranks among the lowest, with only 0.22% citizens having access to opioids for pain relief. While ensuring availability of prescription opioids for pain relief is crucial, it needs close monitoring and regulation as epidemic of prescription opioid misuse was fuelled by illicit marketing of pharmaceutical opioids. Enforcing stricter control has shown plateauing of the misuse and consequences in the US. However, various pros and cons are associated with strict control of opioids like shift to more illicit opioid use (like heroin, fentanyl from illicit drug market) and harmful routes of administration like injecting or insufflating. Stricter enforcement of control of pharmaceutical opioids (licit and illicit marketing) with regular monitoring of the outcomes is necessary, also simultaneous ensuring increased availability and accessibility of treatment for opioid dependent individuals. So the debate on prescription opioid control is ongoing and calls for further discussion in how to regulate the control as well as ensure availability to those who are in genuine need of the same.

Mirogabalin as a Novel Gabapentinoid for the Treatment of Chronic Pain Conditions: An Analysis of Current Evidence.

Neuropathic pain is a challenge for physicians to treat and often requires a multimodal approach with both pharmacologic and lifestyle interventions. Mirogabalin, a potent, selective ligand of the α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels (VGCCs), provides analgesia by inhibiting neurotransmitter release at the presynaptic end of the neuron. Mirogabalin offers more sustained analgesia than its gabapentinoid counterparts in addition to a wider safety margin for adverse events. Recent clinical trials of mirogabalin have demonstrated both efficacy and tolerability of the drug for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia, leading to its approval in Japan. While still not yet FDA approved, mirogabalin is still in its infancy and offers potential into the treatment of neuropathic pain and its associated comorbidities.

Frequency Rhythmic Electrical Modulation System (FREMS) to alleviate painful diabetic peripheral neuropathy: A pilot, randomised controlled trial (The FREMSTOP study).

Frequency Rhythmic Electrical Modulated System (FREMS) is a non-invasive treatment for chronic pain conditions, but its place in the treatment algorithm for painful diabetic peripheral neuropathy (PDPN) is unknown. A pilot, open-label, randomised controlled trial in individuals with PDPN inadequately controlled on at least dual neuropathic pain treatments recruited from primary and secondary care. Participants were randomised 1:1 to FREMS+usual care (n=13) versus usual care (n=12). Primary outcome was change from baseline in perceived pain (assessed by visual analogue scale) at 12weeks between treatment groups. Of 25 participants, 14 (56%) were men, and 21 (84%) were White Europeans. Median (IQR) age and duration of diabetes were 64 (56, 68) and 14 (10, 20) years, respectively. At 12weeks, FREMS showed improvements in perceived pain compared with baseline, although the change was not statistically significant from control group (-4.0[-5.0,0.4] vs. 0[-0.3,0.7], p=0.087). There were significant improvements in pain with FREMS, assessed by McGill Pain questionnaire (p=0.042) and Douleur neuropathique-4 questionnaire (p=0.042). More participants on FREMS had greater than 30 percent reductions in perceived pain compared with controls [7/13(54%) vs 0/12(0%), p=0.042] and significant improvements in Patient Global Impression of Change (p=0.005). FREMS intervention had moderate benefits in quality of life, sleep, depression and pain medication use, but these were not statistically significant. FREMS might be used to treat individuals with PDPN inadequately controlled on two classes of neuropathic pain medications and is associated with improvements in pain severity and perceived impact of treatment. A larger, appropriately designed trial assessing its impact in this population is needed.

The Effect of Medical Cannabis on Pain Level and Quality of Sleep among Rheumatology Clinic Outpatients.

Introduction Medical cannabis (MC) is becoming increasingly popular for the treatment of chronic pain conditions. In this study, we evaluated the effect of MC treatment on pain level and quality of sleep of patients with different medical conditions at the rheumatology clinic. Methods Patients licensed for the use of MC at the rheumatology clinics at different settings were located and contacted. Their demographic and clinical parameters were documented, including type of medical cannabis consumed, way of consumption, and current monthly consumed amount. These patients were contacted by phone and asked about the effect on pain level and quality of sleep. Results A total of 351 patients were located, and 319 completed the questionnaire. Mean age was 46 ± 12 years, 76% were female, 82% had fibromyalgia, ∼9% had mechanical problems, ∼4% had inflammatory problems, ∼4% had neurological problems, and ∼1% had other problems. The average monthly consumed dose of MC was 31, 35, 36, and 32 g, with mean pain level reduction of 77%, 82%, 83%, and 57%, and mean sleep quality improvement of 78%, 71%, 87%, and 76% among patients with fibromyalgia, mechanical, neuropathic, and inflammatory problems, respectively. Mean THC and CBD contents were 18.38% ± 4.96 and 2.62% ± 4.87, respectively. The THC concentration, duration of MC consumption, and MC consumption dose had independent significant correlations with pain reduction while only the duration of MC consumption had an independent significant correlation with sleep quality improvement. Conclusions MC had a favorable effect on pain level and quality of sleep among all spectrums of problems at the rheumatology clinic.

Chronic Pain in the Elderly: Mechanisms and Distinctive Features

Background: Chronic pain is a major issue affecting more than 50% of the older population and up to 80% of nursing homes residents. Research on pain in the elderly focuses mainly on the development of clinical tools to assess pain in patients with dementia and cognitive impairment or on the efficacy and tolerability of medications. In this review, we searched for evidence of specific pain mechanisms or modifications in pain signals processing either at the cellular level or in the central nervous system. Methods: Narrative review. Results: Investigation on pain sensitivity led to conflicting results, with some studies indicating a modest decrease in age-related pain sensitivity, while other researchers found a reduced pain threshold for pressure stimuli. Areas of the brain involved in pain perception and analgesia are susceptible to pathological changes such as gliosis and neuronal death and the effectiveness of descending pain inhibitory mechanisms, particularly their endogenous opioid component, also appears to deteriorate with advancing age. Hyperalgesia is more common at older age and recovery from peripheral nerve injury appears to be delayed. In addition, peripheral nociceptors may contribute minimally to pain sensation at either acute or chronic time points in aged populations. Conclusions: Elderly subjects appear to be more susceptible to prolonged pain development, and medications acting on peripheral sensitization are less efficient. Pathologic changes in the central nervous system are responsible for different pain processing and response to treatment. Specific guidelines focusing on specific pathophysiological changes in the elderly are needed to ensure adequate treatment of chronic pain conditions.