BACKGROUND: Chronic primary pain (CPP) as a diagnosis has been introduced in the recent International Classification of Diseases, 11th Revision (ICD-11). CPP captures the experience of pain as the primary problem, without an underlying attributable cause. Dissemination of UK guidance regarding CPP represents the first time it has been recognised as a condition in its own right. Little is known regarding General Practitioner (GP) views concerning caring for patients with CPP and how related guidance is viewed and applied in practice.
OBJECTIVE: To explore GP perspectives in relation to caring for people with CPP, including challenges encountered and use of related guidelines in practice.
METHODS: A UK-wide qualitative interview study in primary care.
METHODS: Purposive and snowball sampling were used to recruit 15 GP participants from England, Northern Ireland, Wales and Scotland. Semi-structured interviews were undertaken and analysed using reflexive thematic analysis.
RESULTS: Three main themes were generated: (1) \"How to start? Problematic beginnings\" referred to difficulties regarding diagnosis; (2) \"Where to go? Mapping the management challenge\" and (3) \"How to get there? Navigating strategies and response\", explored GP awareness and acceptability of UK guidelines for chronic pain. Areas identified for potential improvement included increased access to NPM and secondary care services, support with de-prescribing and an expanded multidisciplinary team input.
CONCLUSIONS: CPP is complex to both diagnose and manage. Although guidelines provide a useful framework, they pose challenges when translating into day-to-day practice.

Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.

Interstitial cystitis (IC) presents as a chronic pain condition with variable combinations of symptoms depending on the species and individual patient. It is diagnosed by the presence of lower urinary tract signs and symptoms in combination with a variety of comorbid health problems, a history of life adversities, and the absence of other conditions that could cause the lower urinary tract signs. IC occurs naturally in humans and cats as a dimensional condition, with patients presenting with mild, moderate, and severe symptoms. Most patients appear to recover without specific treatment. A number of rodent models of IC have been used to study its causes and treatments. Unfortunately, current therapies generally fail to ameliorate IC symptoms long-term. The recent classification of IC as a chronic primary pain disorder calls for a rethinking of current clinical and research approaches to it. Beginning when a patient encounters a clinician, precipitating, perpetuating, and palliating risk factors can be addressed until a cause or reliably effective therapy is identified, and identifying predisposing and preventive factors can inform epidemiological studies and health promotion interventions. Predisposing, precipitating, and perpetuating risk factors, including environmental, psychological, and biological, increase the activity of the central threat response system (CTRS), which plays a clinically important role in IC symptoms. Studies in cats and rodent models have revealed that environmental enrichment (EE), in the absence of bladder-directed therapies, leads to amelioration of IC symptoms, implying a central role for the CTRS in symptom precipitation and perpetuation. Conceptually moving the source of IC pain to the brain as a motivational state rather than one resulting from peripheral nociceptive input offers both clinicians and researchers novel opportunities to improve care for patients with IC and for researchers to use more ecologically valid rodent models. It may even be that IC results from an excess of risk to protective factors, making this imbalance a targetable cause rather than a consequence of IC.

Previous evidence suggested that chronic pain is characterized by cognitive deficits, particularly in the social cognition domain. Recently, a new chronic pain classification has been proposed distinguishing chronic primary pain (CPP), in which pain is the primary cause of patients\' disease, and chronic secondary pain (CSP), in which pain is secondary to an underlying illness. The present study aimed at investigating social cognition profiles in the two disorders. We included 38 CPP, 43 CSP patients, and 41 healthy controls (HC). Social cognition was assessed with the Ekman-60 faces test (Ekman-60F) and the Story-Based Empathy Task (SET), whereas global cognitive functioning was measured with the Montreal Cognitive Assessment (MoCA). Pain and mood symptoms, coping strategies, and alexithymia were also evaluated. Correlations among clinical pain-related measures, cognitive performance, and psychopathological features were investigated. Results suggested that CSP patients were impaired compared to CPP and HC in social cognition abilities, while CPP and HC performance was not statistically different. Pain intensity and illness duration did not correlate with cognitive performance or psychopathological measures. These findings confirmed the presence of social cognition deficits in chronic pain patients, suggesting for the first time that such impairment mainly affects CSP patients, but not CPP. We also highlighted the importance of measuring global cognitive functioning when targeting chronic pain disorders. Future research should further investigate the cognitive and psychopathological profile of CPP and CSP patients to clarify whether present findings can be generalized as disorder characteristics.

BACKGROUND: Chronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown.
METHODS: Based on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro.
RESULTS: Intrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol.
CONCLUSIONS: In the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.

Chronic back or neck pain (CBNP) can be primary (nociplastic or neuroplastic; without clear peripheral etiology) or secondary (to nociceptive or neuropathic causes). Expanding on available models of nociplastic pain, we developed a clinic-ready approach to diagnose primary/nociplastic pain: first, a standard physical exam and review of imaging to rule out secondary pain; and second, a detailed history of symptom presentation to rule in primary pain. We trained a physician who evaluated 222 patients (73.9% female, age M = 59.6) with CBNP; patients separately completed pain and psychosocial questionnaires. We estimated the prevalence of primary CBNP and explored biomedical, imaging, and psychological correlates of primary CBNP. Although almost all patients (97.7%) had at least 1 spinal anomaly on imaging, the diagnostic approach estimated that 88.3% of patients had primary pain, 5.0% had secondary pain, and 6.8% had mixed pain. Patients with primary pain were more likely than the other 2 groups of patients (combined as \"non-primary pain\") to report certain functional conditions, central sensitization, and features such as sensitivity to light touch, spreading pain, and pain worsening with stress; however, no difference was detected in depression, anxiety, and pain catastrophizing between those with primary and nonprimary pain. These findings are consistent with prior estimates that 85 to 90% of CBNP is \"nonspecific.\" Further research is needed to validate and perhaps refine this diagnostic approach, which holds the potential for better outcomes if patients are offered treatments targeted to primary pain, such as pain neuroscience education and several emerging psychological therapies. PERSPECTIVE: We developed an approach to diagnose chronic primary pain, which was applied in a physiatry clinic to 222 patients with CBNP. Most patients (88.3%) had primary pain, despite almost universal anomalies on spinal imaging. This diagnostic approach can guide educational and psychological treatments tailored for primary pain.

BACKGROUND: The term \"nature-based sensory stimuli\" refers to the sensory information produced by biotic and abiotic agents from natural environments. The literature has reported the beneficial effects of these agents on various pain dimensions in non-clinical populations.
OBJECTIVE: To evaluate the potential analgesic effects of nature-based multisensory stimulation in women with fibromyalgia syndrome.
METHODS: A randomized, double-blind, placebo-controlled, parallel-group trial with a 1:1 allocation ratio was conducted. Forty-two women with fibromyalgia syndrome interacted with either different plant species with flowers, stones, and soil organic matter or their synthetic imitations for 30 minutes. Outcome measurements were performed before and after the intervention, including clinical pain intensity using the Numeric Rating Scale, cold pain thresholds using the Cold Pressor Test, mechanical hyperalgesia and wind-up using a monofilament, and pressure pain thresholds using a pressure algometer.
RESULTS: Analyses revealed group × time interactions for clinical pain intensity (F = 7.915, p = .008), cold-water immersion time (F = 7.271, p = .010), mechanical hyperalgesia (F = 4.701, p = .036), and pressure pain threshold (p ≤ .017). Between-group differences were found in clinical pain intensity (p = .012), cold pain thresholds (p = .002), and pressure pain thresholds (p < .05). The experimental group exhibited reduced clinical pain intensity (p = .001) and increased pressure pain thresholds (p ≤ .034).
CONCLUSIONS: Women with fibromyalgia syndrome may benefit from multisensory stimulation using biotic and abiotic agents from natural environments for 30 minutes. Interacting with flowering plants and soil components appears to induce analgesic effects.

Chronic pain is a common comorbidity in those with functional neurological disorder (FND); however, the prevalence and characteristics of FND in those with chronic pain is unknown.
A retrospective electronic records review was made of consecutive new patients attending a chronic pain clinic of a regional service. Clinical features, medication for and outcome of chronic pain, any lifetime diagnoses of functional disorders, FND, and psychiatric disorders, and undiagnosed neurological symptoms were recorded.
Of 190 patients attending the chronic pain clinic, 32 (17%) had a lifetime diagnosis of FND and an additional 11 (6%) had undiagnosed neurological symptoms. Pain patients with comorbid FND were more likely to have chronic primary pain (88% with FND, 44% without FND, p < 0.0001), widespread chronic primary pain (53%, 15%, p < 0.00001), and depression (84%, 52%, p < 0.005) and less likely to have a pain-precipitating event (19% vs. 56%, p < 0.001). However, there was no significant difference between these patients in opiate prescription, benzodiazepine prescription, or pain outcome.
This first study of FND in a chronic pain patient population found a remarkably high prevalence of FND (17%) and is possibly an underestimation. The size of the overlap indicates that FND and chronic pain research fields are likely to have a lot to learn from each other.

As motivation for psychological treatment at intake has been shown to predict favorable outcomes after an inpatient stay, this study aimed to further characterize the different components of psychological treatment motivation that predict favorable treatment outcomes. 294 inpatients with chronic primary pain participating in an interdisciplinary multimodal pain treatment in a tertiary psychosomatic university clinic completed a battery of psychological questionnaires at intake and discharge. Treatment motivation was assessed at intake using the scales of the FPTM-23 questionnaire, while pain intensity, pain interference, anxiety, and depression were assessed both at intake and discharge. After treatment, pain intensity, pain interference, anxiety, and depression were significantly reduced. While higher levels on the FPTM-23 scale of suffering predicted smaller decreases in anxiety after treatment, higher scores on the scale of hope, i.e., lower levels of hopelessness, predicted lower levels of pain interference, anxiety, and depression after treatment. None of the scales of treatment motivation predicted pain intensity levels after treatment. Above and beyond providing symptom relief, reducing hopelessness and fostering hope regarding the treatment process and outcome might help clinicians treat patients with chronic primary pain more effectively.

Most patients suffering from chronic pain are more susceptible to pain and pressure due to higher pain sensitivity. Since psychosocial factors play a central role in developing and maintaining chronic pain, investigating associations between pain sensitivity and psychosocial stressors promises to advance the biopsychosocial understanding of chronic pain.
We aimed to replicate Studer et al.\'s (2016) findings about associations of psychosocial stressors with pain sensitivity in a new sample of patients with chronic primary pain (ICD-11, MG30.0).
A pain provocation test was used on both middle fingers and earlobes to assess pain sensitivity among 460 inpatients with chronic primary pain. Potentially life-threatening accidents, war experiences, relationship problems, certified inability to work, and adverse childhood experiences were assessed as potential psychosocial stressors. Structural equation modeling was used to investigate associations between psychosocial stressors and pain sensitivity.
We partially replicated Studer et al.\'s findings. Similar to the original study, patients with chronic primary pain showed enhanced pain sensitivity values. Within the investigated group, war experiences (β = 0.160, p < .001) and relationship problems (β = 0.096, p = .014) were associated with higher pain sensitivity. In addition, the control variables of age, sex, and pain intensity also showed a predictive value for higher pain sensitivity. Unlike Studer et al., we could not identify a certified inability to work as a predictor of higher pain sensitivity.
This study showed that beyond age, sex, and pain intensity, the psychosocial stressors of war experiences and relationship problems were associated with higher pain sensitivity.