Most patients with multiple myeloma (MM) suffer from chronic pain at every stage of the natural disease process. This review focuses on the most common causes of chronic pain in MM patients: (1) pain from myeloma bone disease (MBD); (2) chemotherapy-induced peripheral neuropathy as a possible consequence of proteasome inhibitor therapy (i.e., bortezomib-induced); (3) post-herpetic neuralgia as a possible complication of varicella zoster virus reactivation because of post-transplantation immunodepression; and (4) pain in cancer survivors, with increasing numbers due to the success of antiblastic treatments, which have significantly improved overall survival and quality of life. In this review, non-pain specialists will find an overview including a detailed description of physiopathological mechanisms underlying central sensitization and pain chronification in bone pain, the rationale for the correct use of analgesics and invasive techniques in different pain syndromes, and the most recent recommendations published on these topics. The ultimate target of this review was to underlie that different types of pain can be observed in MM patients, and highlight that only after an accurate pain assessment, clinical examination, and pain classification, can pain be safely and effectively addressed by selecting the right analgesic option for the right patient.

The aim of the study was to analyse intraoral neurophysiological changes in patients with unilateral lingual nerve lesions as well as patients with Burning Mouth Syndrome (BMS) by applying a standardized Quantitative Sensory Testing (QST) protocol. The study included patients suffering from a peripheral lesion of the lingual nerve (n = 4), from BMS (n = 5) and healthy controls (n = 8). Neurophysiological tests were performed in the innervation areas of the tongue bilaterally. For BMS patients the dorsal foot area was used as reference. For patients with peripheral lesion of the lingual nerve the affected side of the tongue showed increased thresholds for thermal (p < 0.05–0.001) and mechanical (p < 0.01–0.001) QST parameters, indicating a hypoesthesia and thermal hypofunction. In BMS patients, a pinprick hypoalgesia (p < 0.001), a cold hyperalgesia (p < 0.01) and cold/warmth hypoesthesia (p < 0.01) could be detected. The results of this study verified the lingual nerve lesion in our patients as a peripheral dysfunction. The profile showed a loss of sensory function for small and large fibre mediated stimuli. A more differentiated classification of the lingual nerve injury was possible with QST, regarding profile, type and severity of the neurologic lesion. BMS could be seen as neuropathy with variable central and peripheral contributions among individuals resulting in chronic pain.

Defined by dysfunction or degeneration of Aδ and C fibers, small fiber neuropathies (SFNs) entail a relevant health burden. In 50% of cases, the underlying cause cannot be identified or treated. In 100 individuals (70% female individuals; mean age: 44.8 years) with an idiopathic, skin biopsy–confirmed SFN, we characterized the symptomatic spectrum and measured markers of oxidative stress (vitamin C, selenium, and glutathione) and inflammation (transforming growth factor beta, tumor necrosis factor alpha), as well as neurotoxic 1-deoxy-sphingolipids. Neuropathic pain was the most abundant symptom (95%) and cause of daily life impairment (72%). Despite the common use of pain killers (64%), the painDETECT questionnaire revealed scores above 13 points in 80% of patients. In the quantitative sensory testing (QST), a dysfunction of Aδ fibers was observed in 70% and of C fibers in 44%, affecting the face, hands, or feet. Despite normal nerve conduction studies, QST revealed Aβ fiber involvement in 46% of patients' test areas. Despite absence of diabetes mellitus or mutations in SPTLC1 or SPTLC2, plasma 1-deoxy-sphingolipids were significantly higher in the sensory loss patient cluster when compared with those in patients with thermal hyperalgesia (P < 0.01) or those in the healthy category (P < 0.1), correlating inversely with the intraepidermal nerve fiber density (1-deoxy-SA: P < 0.05, 1-deoxy-SO: P < 0.01). Patients with arterial hypertension, overweight (body mass index > 25 kg/m²), or hyperlipidemia showed significantly lower L-serine (arterial hypertension: P < 0.01) and higher 1-deoxy-sphingolipid levels (arterial hypertension: P < 0.001, overweight: P < 0.001, hyperlipidemia: P < 0.01). Lower vitamin C levels correlated with functional Aβ involvement (P < 0.05). Reduced glutathione was lower in patients with Aδ dysfunction (P < 0.05). Idiopathic SFNs are heterogeneous. As a new pathomechanism, plasma 1-deoxy-sphingolipids might link the metabolic syndrome with small fiber degeneration.

Introduction: Studies have reported autonomic impairment in patients with idiopathic REM sleep behaviour disorder (iRBD), which is considered a prodromal stage of alpha-synucleinopathies. It is still debated whether central or peripheral pathologies are first manifestations of alpha-synucleinopathies. This study aimed to characterize autonomic and somatosensory function in iRBD patients. Methods: This cross-sectional prospective case–control study included 17 iRBD patients (mean age 66.3 ± 9.2 years) and 16 healthy controls (HCs, 66.6 ± 11.3 years). Quantitative sensory testing, neurological and neuropsychological assessments, norepinephrine blood plasma levels, tilt table examination with orthostatic blood pressure, and heart rate variability were carried out. Longitudinal data of 10 iRBD patients, including neurological, neuropsychological, and tilt table examination, were assessed. Results: iRBD patients more frequently presented with orthostatic dysfunction than HCs (70.6% vs. 6.3%, p < 0.0001). Supine norepinephrine plasma levels were normal, but lower in iRBD (249.59 ± 99.78 pg/ml iRBD, 354.13 ± 116.38 pg/ml HCs, p < 0.05). Quantitative sensory testing revealed impaired cold (CDT) and vibration detection thresholds (VDT) on the foot in iRBD (CDT foot iRBD − 1.24 ± 0.31, HCs − 9.89E-17 ± 0.25, VDT iRBD − 1.11 ± 0.47, HCs − 1.46E-16 ± 0.25, p < 0.05). Cold detection thresholds differed between the foot and hand among iRBD patients (foot − 1.24 ± 0.31, hand − 0.56 ± 0.25, p < 0.05). Longitudinal data revealed an increase in maximum systolic and diastolic orthostatic blood pressure changes and a decrease in the Valsalva ratio in the follow-up group (p < 0.05). Conclusion: This study revealed autonomic dysfunction with somatosensory impairment, and decreased norepinephrine levels in iRBD, which may serve as a possible prodromal marker for developing alpha-synucleinopathy.

Myopathies fall under the umbrella of rare diseases, however, muscle pain is a relevant, under-recognized symptom with limited treatment options. Carbamazepine is an oral sodium channel blocker approved for the treatment of seizures and neuropathic pain. In 54 individuals receiving carbamazepine for muscle pain, we retrospectively assessed the subjective treatment response, side effects, and reasons for carbamazepine discontinuation. The underlying diagnoses leading to muscle pain were diverse, ranging from metabolic (n = 5) and other hereditary (n = 9) to acquired (n = 2) myopathies and myotonia syndromes (n = 22). Under carbamazepine (daily dose 254 ± 138 mg), patients reported a significant reduction of pain, quantified by an 11-point numeric rating scale (−1.9 ± 1.8, p < 0.001). Compared to age- and sex-matched controls, our sensory assessment revealed a significant dysfunction of Aδ-nerve fibers in patients with chronic muscle pain. Neuropathic pain components identified by the painDETECT questionnaire or quantitative sensory testing did not seem to influence the reported treatment response. Side effects (n = 18) such as fatigue, elevated liver enzymes, and diarrhea, as well as lack of pain improvement (n = 6), led to carbamazepine discontinuation in 44.4% (24/54). Mediated by dysfunctional Aδ-nerve fibers, muscle pain is common in a variety of myopathies. Carbamazepine may reduce pain levels, but comes with therapy-limiting side effects.

Pain sensitivity of healthy subjects in the cold-pressor (CP) test was proposed to be dichotomously distributed and to represent a pain sensitivity trait. Still, it has not been systematically explored which factors influence this pain sensitivity readout. The aim of this study was to distinguish potential contributions of local tissue-related factors such as perfusion and thermoregulation or gain settings in nociceptive systems. Cold-pressor–sensitive and CP-insensitive students screened from a medical student laboratory course were recruited for a CP retest with additional cardiovascular and bilateral local vascular monitoring. In addition, comprehensive quantitative sensory testing according to Deutscher Forschungsverbund Neuropathischer Schmerz standards and a sustained pinch test were performed. Cold pressor was reproducible across sessions (Cohen kappa 0.61 ± 0.14, P < 0.005). At 30 seconds in ice water, CP-sensitive subjects exhibited not only more pain (78.6 ± 26.3 vs 29.5 ± 17.5, P < 0.0001) but also significantly stronger increases in mean arterial blood pressure (12.6 ± 9.3 vs 5.6 ± 8.1 mm Hg, P < 0.05) and heart rate (15.0 ± 8.2 vs 7.1 ± 6.2 bpm, P < 0.005), and lower baroreflex sensitivity, but not local or vasoconstrictor reflex–mediated microcirculatory responses. Cold-pressor–sensitive subjects exhibited significantly lower pain thresholds also for cold, heat, and blunt pressure, and enhanced pain summation, but no significant differences in Aδ-nociceptor–mediated punctate mechanical pain. In conclusion, differences in nociceptive signal processing drove systemic cardiovascular responses. Baroreceptor activation suppressed pain and cardiovascular responses more efficiently in CP-insensitive subjects. Cold-pressor sensitivity generalized to a pain trait of C-fiber–mediated nociceptive channels, which was independent of local thermal and vascular changes in the ice-water–exposed hand. Thus, the C-fiber pain trait reflects gain setting of the nociceptive system.