Patient with pain and depression – practical therapeutic implications

Depression and pain are often coexisting phenomena, and the relationship between both phenomena is two-way – the occurrence of depression increases the risk of pain, and both acute and chronic pain increase the risk of depression. Pain may be part of the clinical picture of depression, be a result of comorbid psychiatric disorders, be associated with comorbidities, be a chronic pain syndrome, or be a complication of pharmacotherapy. The comorbidity of pain and depression is associated with a worse prognosis, lower therapeutic response, lower quality of life, impaired functioning, and a greater risk of relapse and suicide. There are indications that the same structures and neurotransmitters are involved in the pathophysiology of pain and depression, which may explain the coanalgesic effect of some antidepressants. The drugs with the best proven effectiveness are serotonin and noradrenaline reuptake inhibitors (especially duloxetine) and amitriptyline. Other drugs that may be of use in the treatment of pain are mirtazapine, mianserin, trazodone, agolemelatine, bupropion, and moclobemide. Selective serotonin reuptake inhibitors are used primarily in the treatment of depression symptomatic pain, but there is little evidence that they are effective in other types of pain. The use of certain psychotropic drugs, incl. SSRIs, clomipramine, benzodiazepines, Z drugs, and anticholinergics may be associated with increased pain. Caution is required when using polypharmacy in the form of a combination of an antidepressant and an analgesic because of the risk of worsening side effects or loss of treatment effectiveness. In the case of opioid drugs, in particular tramadol, the combination with drugs with a serotonergic effect may be associated with the risk of serotonin syndrome.

The German Guidelines for the treatment of anxiety disorders: first revision

Starting in 2019, the 2014 German Guidelines for Anxiety Disorders (Bandelow et al. Eur Arch Psychiatry Clin Neurosci 265:363–373, 2015) have been revised by a consensus group consisting of 35 experts representing the 29 leading German specialist societies and patient self-help organizations. While the first version of the guideline was based on 403 randomized controlled studies (RCTs), 92 additional RCTs have been included in this revision. According to the consensus committee, anxiety disorders should be treated with psychotherapy, pharmacological drugs, or their combination. Cognitive behavioral therapy (CBT) was regarded as the psychological treatment with the highest level of evidence. Psychodynamic therapy (PDT) was recommended when CBT was not effective or unavailable or when PDT was preferred by the patient informed about more effective alternatives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are recommended as first-line drugs for anxiety disorders. Medications should be continued for 6–12 months after remission. When either medications or psychotherapy were not effective, treatment should be switched to the other approach or to their combination. For patients non-responsive to standard treatments, a number of alternative strategies have been suggested. An individual treatment plan should consider efficacy, side effects, costs and the preference of the patient. Changes in the revision include recommendations regarding virtual reality exposure therapy, Internet interventions and systemic therapy. The recommendations are not only applicable for Germany but may also be helpful for developing treatment plans in all other countries.

Gut Microbiome Alteration after Reboxetine Administration in Type-1 Diabetic Rats

Antidepressants are drugs commonly used in clinical settings. However, there are very limited studies on the effects of these drugs on the gut microbiota. Herein, we evaluated the effect of reboxetine (RBX), a selective norepinephrine (noradrenaline) reuptake inhibitor (NRI), on gut microbiota in both diabetic and non-diabetic rats. This is the first report of relation between reboxetine use and the gut microbiota to our knowledge. In this study, type-1 diabetes induced by using streptozotocin (STZ) and RBX was administered to diabetic rats and healthy controls for 14 days. At the end of the treatment, stool samples were collected. Following DNA extraction, amplicon libraries for the V3-V4 region were prepared and sequenced with the Illumina Miseq platform. QIIME was used for preprocessing and analysis of the data. As a result, RBX had a significant effect on gut microbiota structure and composition in diabetic and healthy rats. For example, RBX exposure had a pronounced microbial signature in both groups, with a low Firmicutes/Bacteroidetes ratio and low Lactobacillus levels. While another abundance phylum after exposure to RBX was Proteabacteria, other notable taxa in the diabetic group included Flavobacterium, Desulfovibrionaceae, Helicobacteriaceae, Campylobacterales, and Pasteurellacae when compared to the untreated group.

Management issues in neuropathic pain

Neuropathic pain is a common complication to cancer and cancer treatments, such as surgery, chemotherapy, and radiation therapy. Neuropathic pain may be present in up to 40% of cancer patients and may persist independently of the cancer and affect the quality of life in disease-free cancer survivors. Particular surgery and chemotherapy may cause chronic neuropathic pain in cancer survivors. The diagnosis of neuropathic pain can be challenging and requires documentation of a nervous system lesion and pain in areas of sensory changes. The pharmacological treatment includes tricyclic antidepressants, selective serotonin–noradrenaline reuptake inhibitors (duloxetine or venlafaxine), gabapentin, and pregabalin as first-line treatments. Topical lidocaine 5%, capsaicin 8% patches, botulinum toxin type A, tramadol, and strong opioids are second- and third-line treatments. Steroids may have a role in the acute management of cancer-related neuropathic pain. Due to limited efficacy or intolerable side effects at maximal doses, combination therapy is often required and careful monitoring of effect and adverse reactions is important.

Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes

Apathy is a debilitating feature of many diseases, including Parkinson's disease. We tested the hypothesis that degeneration of the locus coeruleus-noradrenaline system contributes to apathy by modulating the relative weighting of prior beliefs about action outcomes. Participants with mild-to-moderate idiopathic Parkinson's disease (N=17) completed a double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity.

Nutritional Supplements for the Treatment of Neuropathic Pain

Neuropathic pain affects 7–10% of the population and is often ineffectively and incompletely treated. Although the gold standard for treatment of neuropathic pain includes tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors, and anticonvulsants, patients suffering from neuropathic pain are increasingly turning to nonpharmacologic treatments, including nutritional supplements for analgesia. So-called “nutraceuticals” have garnered significant interest among patients seeking to self-treat their neuropathic pain with readily available supplements. The supplements most often used by patients include vitamins such as vitamin B and vitamin D, trace minerals zinc and magnesium, and herbal remedies such as curcumin and St. John’s Wort. However, evidence surrounding the efficacy and mechanisms of these supplements in neuropathic pain is limited, and the scientific literature consists primarily of preclinical animal models, case studies, and small randomized controlled trials (RCTs). Further exploration into large randomized controlled trials is needed to fully inform patients and physicians on the utility of these supplements in neuropathic pain. In this review, we explore the basis behind using several nutritional supplements commonly used by patients with neuropathic pain seen in rheumatology clinics.

The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.

Depression and Pain: use of antidepressant

Background: Emotional disorders are common comorbid affectations that exacerbate the severity and persistence of chronic pain. Specifically, depressive symptoms can lead to an excessive duration and intensity of pain. The use of antidepressant drugs is associated with pain reduction. The recent development of animal models has accelerated studies focusing on the underlying mechanisms of chronic pain and depression comorbidity. Aim: This review provides an overview of the comorbid relationship of chronic pain and depression, the clinical and pre-clinical studies performed on the neurobiological aspects of pain and depression, and the use of antidepressants as analgesics. Method: A systematic search of literature databases was conducted according to the pre-defined criteria. The authors independently conducted a focused analysis of the full-text articles. Results: Studies suggest that pain and depression are highly-intertwined and may co-exacerbate physical and psychological symptoms. One important biochemical basis for pain and depression focuses on the serotonergic and norepinephrine system, which have been shown to play an important role in this comorbidity. Brain structures that codify pain are also involved in mood. It is evident that using serotonergic and norepinephrine antidepressants are strategies commonly employed to mitigate pain. Conclusion: Literature indicates that pain and depression impact each other and play a prominent role in the development and maintenance of other chronic symptoms. Antidepressants continue to be a major therapeutic tool for managing chronic pain. Tricyclic antidepressants (TCAs) are more effective in reducing pain than selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs).