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6. Management of the Central Nervous System Chronic Pelvic Pain
Keywords
Chronic pelvic painCentral nervous systemCentral sensitizationPharmacological therapyChronic pelvic pain (CPP) is a syndrome characterized by persistent pain lasting longer than 6 months, or recurrent and noncyclic episodes of abdominal/pelvic pain, hypersensitivity, or discomfort often associated with lower urinary tract, sexual, bowel, pelvic floor, or gynecological dysfunction and emotional consequences, often in the absence of an organic etiology [1].
Despite its high prevalence (CPP affects approximately 15–20% of women in the USA) and its negative impact on quality of life (QoL), little is known about the mechanisms underlying CPP [2]. The impact and burden of CPP to patients are enormous. CPP patients suffer from considerable morbidity throughout their lives, with a resulting, significant decrease in QoL which may affect also their partners. Chronic pelvic pain syndromes (CPPS) are multifactorial and multidisciplinary conditions [3] with possible sources of pain located in the urogynecological, gastrointestinal, and musculoskeletal tract, and/or in the nervous system (NS) [4].
CPP mechanisms may include ongoing acute peripheral pain mechanisms involving somatic or visceral tissue and/or chronic pain mechanisms, which especially involve the central nervous system (CNS; [5]). As of peripheral pain mechanisms, inflammatory pain results from the increased excitability of peripheral nociceptive sensory fibers produced by the action of inflammatory mediators. The release of substance P and other neurotransmitters, and gross mast cell activation, results in neurogenic inflammation [6]. This excitatory effect, in turn, is a result of the altered activity of ion channels within affected sensory fibers [7]. Activation of acute pain mechanisms by a nociceptive event may sensitize peripheral nociceptive afferents, magnifying the afferent signalling [8, 9]. When pain becomes long-lasting and the afferent signaling from the periphery to CNS continues to be over-functioning, a central sensitization (CS) can occur, although the initial injury can be completely disappeared [10]. The peripheral sensitization is a local event, while CS is a central phenomenon of the NS with the enhanced responsiveness of the central neurons to input from unimodal and polymodal receptors and there is no ongoing nociceptive stimulation from the periphery [11]. This central hypersensitivity could clarify the presence of chronic pain in the absence of a recognized peripheral pathology [12]. A continuous pain signal from the pelvis may result in a dysfunctional CNS response know as central pain amplification [13]. The “widespread pain” may be independent of pain severity and could imply a restructuring of pain processing at the level of the brain.
6.1 Neuroimaging
The mechanisms contributing to pain amplification and chronicity are heterogeneous and likely occur at various levels of the NS. Tests that look at brain structure and function (e.g., neuroimaging studies) can help diagnosis and define certain pain conditions. Types of neuroimaging tests include computed tomography, magnetic resonance imaging (MRI), and positron-emission tomography. In pelvic pain conditions, functional MRIs may be used to confirm symptoms in patients suffering from painful conditions. Neuroimaging techniques using MRI have allowed the detailed description of the brain in patients with CPP. Alterations in structural brain regions and regional connectivity are associated with pain perception and modulation in the affected patients. A decrease in gray matter density/volume in the thalamus, cingulate cortex, insular cortex, and cerebellum has been demonstrated in patients with chronic pain syndromes [2]. Moreover, alterations in regional brain morphology have been hypothesized to be responsible not only for the development and/or maintenance of pain but also for other common characteristics, such as mood disorders and cognitive impairment [14]. Kutch et al. demonstrated an increasing gray matter volume from the localized to intermediate and to widespread pain groups within several sensorimotor areas; moreover, the functional interaction between 37 pairs of brain regions increased significantly in CPP patients with widespread pain as compared to localized type [15].
6.2 Patient Assessment: Symptoms and Signs in Chronic Pelvic Pain
The diagnosis of CPP is solely symptomatic and comes from the history of pain perceived in the region of the pelvis, in the absence of other pathologies. Medical history and physical examination are the most important steps to understand better the patient’s perception of his/her pain. Examination should provide for specific questions about duration, perception, and modality of pain [16]. The onset of symptoms may be either gradual or rapid. Therefore, the diagnosis is based on the exclusion of confusable illness and on the presence of specific combination of symptoms and signs [17].
Common bladder symptoms of CPP include increased daytime and nighttime urinary frequency, urgency, bladder hypersensitivity, bladder discomfort, and bladder pain: these symptoms are collectively called hypersensitive bladder syndrome [18]. According to the ESSIC Guidelines [17], urinary symptoms should be investigated by urinalyses and urine cultures, PSA in males >40 years, uroflowmetry, post-void residual urinary volume by ultrasound scanning, cystoscopy, and bladder wall biopsy.
Questionnaires are validated instruments to assess urinary and sexual dysfunction, pain, disability, fatigue, mood, and sleep disorders [19]. The most frequently used questionnaire for the evaluation of pain, urinary symptoms, and QoL is the O’Leary/Sant (ICSI and ICPI).
In order to classify patients with CPP a 6-point clinical phenotyping system UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, tenderness) has been clinically validated. Each domain is clinically defined and associated with specific therapy [20].
6.3 Treatment
Few well-designed, randomized controlled trials have been conducted until now on different treatment modalities, and this still precludes the development of evidence-based management strategies. Moreover, the majority of pharmacological agents used to treat patients with CPP are still off label [21]. To date, there is general agreement on the use of some agents (orally or intravesically administered) as indicated by the EAU guidelines on chronic pelvic pain [22] and the AUA Guidelines [23]. Severe CPP is difficult to treat and it often requires the use of antidepressants and anticonvulsants due to their additional analgesic properties. Benefit from medications used to control neuropathic pain may provide indirect evidence of the intrinsic nature of chronic pain [24]. The key point includes tailoring therapy to each patient on the basis of localization, severity, frequency, and duration of pain episodes. Thus, phenotyping of the disease condition based on symptom classification such as the UPOINT system is important for the selection of appropriate treatments in individual patients [25].
The management of CPP required a multifaceted approach of the pharmacological therapy due to the multiple levels in the nervous system which act in the mechanism of action of pain. In order to control central sensitization in patients affected by chronic pelvic pain, the EAU Guidelines recommended the following approach:
6.3.1 First-Line Agents
6.3.1.1 Antidepressants
Tricyclic antidepressants (TCA) are a treatment option frequently used for CPP. They act to increase the levels of norepinephrine and serotonin via reuptake inhibition. Higher levels of norepinephrine and serotonin seem to decrease pain sensitivity [26]. There are research evidences that showed the role of amitriptyline in pain control as demonstrated by the study of van Opoven et al. [27]. Foster et al. demonstrated also a great effect of amitriptyline (increasing doses from 10 to 75 mg/day for 12 weeks) in reducing ICSI scores and urinary frequency [28]. Unfortunately, amitriptyline is associated with high rates of anticholinergic side effects, as dry mouth, dizziness, sedation, and constipation that can cause its early discontinuation [29].
Secondary amine tricyclics (e.g., nortriptyline and desipramine) have less anticholinergic side effects, and thus they seem to be preferable in terms of tolerability, although they show a lower effect in reducing painful symptoms [30].
Selective serotonin reuptake inhibitors (SSRI) such as paroxetine or fluoxetine can be used as antipsychotics. Indeed, they are normally used for agitation and delirium but their role in the management of chronic pain is unclear [31].
Other antidepressants (serotonin norepinephrine reuptake inhibitors—SNRI), such as duloxetine or venlafaxine, may have an analgesic effect by centrally increasing the norepinephrine levels. These drugs are usually well tolerated with few side effects but the available data on their efficacy are still very limited. Studies have been performed predominantly in patients with peripheral neuropathic pain and only few data are available for central pain [31].
Few data are actually available about the use of trazodone (serotonin-2 antagonist/reuptake inhibitor); the real benefit of this therapy is that it does not induce sexual dysfunction.
TCAs should be used with caution along with other drugs due to the possible emergence of the serotonin syndrome.
6.3.1.2 Membrane Stabilizers/Anticonvulsants
The mechanism of action of gabapentin and pregabalin is the calcium channel block, decreasing the reuptake of glutamate, substance P, and norepinephrine. These drugs are membrane stabilizers due their effect to reduce the hyperexcitability of nerves centrally and peripherally. Research evidences regarding the efficacy of anticonvulsants in CPP are limited. Sator-Katzenschlager et al. showed in their study that gabapentin improves pain symptoms compared to amitriptyline, with less side effects [32].
6.3.2 Second-Line Agents
6.3.2.1 Opioids
There are no data supporting the use of opioids in patients with CPP [33]. Opioids act directly to the μ or δ receptors that are found in both the central and peripheral nervous systems. Actually, opioids are the second-line therapy of moderate and severe pain. Their use in the treatment of chronic and nonmalignant pain in the long term is strongly discouraged and considered as the last chance. Recent research evidences have highlighted the opioid-induced hyperalgesia effect, a condition where paradoxically patients assuming opioids become more sensitive to certain painful stimuli [34]. Chronic opioid therapy is associated with multiple side effects such as immunosuppression, androgen deficiency (with lowered sex hormones), constipation, and depression [35]. The risk for their misuse must be constantly evaluated.
Other options other than traditional opioid treatment are opioids with a dual-acting components in order to increase their analgesic effect. Tapentadol, for example, is a centrally acting μ-opioid agonist with a norepinephrine reuptake inhibition. This dual mechanism allows for a greater use of the drug with less side effects [36].
6.3.2.2 Tramadol
The analgesic effect of tramadol includes weak μ-opioid agonist activity and weak reuptake inhibition of norepinephrine and serotonin. The Food and Drug Administration (FDA) recently issued a warning indicating that tramadol should be used with caution in older patients with seizures or on drugs that cause serotonin syndrome [37].
6.3.3 Third-Line Agents
6.3.3.1 Cannabinoids
Their features are the low side effect profile and poor risk of drug interactions. Targets for treatment are the two G-protein cannabinoid receptors: cannabinoid 1 (CB1r) and cannabinoid 2 (CB2r) which are strictly involved in pain modulation. Cannabinoid ligands are also important components in nociception of pain. While CB1r is widely expressed in the brain, CB2r is commonly found in the immune system (microglia and monocytes; [38]). Localization of CB1r to neuronal terminals strongly suggests that it plays important roles in regulating synaptic function. CB2r overexpression in microglia and central neurons has been demonstrated in mice with a consequent, genetically mediated improvement in CB2 signaling; conversely, the deletion of CB2r resulted in enhanced neuro-inflammatory response after sciatic nerve transection [39]. No data are available on the efficacy of cannabinoids in the treatment of CPP; few evidences about their use in other chronic pain conditions demonstrated variable effectiveness.
6.3.4 Fourth-Line Agents
6.3.4.1 Antipsychotics
Nix et al. in their meta-analysis on the analgesic potency of antipsychotics showed that only 10 out of 15 studies with a higher statistical power described a possible analgesic effect. None of the studies identified could differentiate between the effect of analgesia and sedation of the drug used. Evidences regarding the efficacy in pain reduction are inadequate and before using this drug as an add-on therapy it is necessary to consider adverse effects.
6.3.4.2 Other Anticonvulsant Agents
Topiramate: Few data are present about anticonvulsant in CPP. Muehlbacher et al. demonstrated the beneficial effects (in terms of pain and health-related quality of life) of topiramate in patients with chronic low back pain [40].
6.3.5 Emerging Therapies
6.3.5.1 Toxins
More recently, botulinum toxin (BTX) has also been used in pain-related disorders (on-label chronic migraine or off-label, such as neuropathic pain or lower back pain). Although BTX was initially considered to alleviate pain through a simple muscle relaxation, recent studies showed that the mechanism of action of BTX in pain relief is more complex [41]. A possible explanation for BTX-modulating pain is represented by its retrograde axonal transport to the CNS. It has been observed that, in addition to local uptake in the synaptic terminal, a distinct secondary uptake pathway results in retrograde transport of the fully active neurotoxin at distal sites. This retrograde axonal transport is followed by a process of cell-to-cell transfer (named trans-cytosis) by which the neurotoxin may gain access to second-order neurons in the CNS [42].
In CCI-exposed mice, BTX-A reduced the following: the number of astrocytes, the percentage of active astrocytes, and the activation of microglia in neuropathic animals after chronic morphine treatment, and it modulates the immune response through a TLR2-dependent pathway in macrophages [43].
6.3.6 Combination Therapies
6.3.6.1 Palmitoylethanolamide
The beginning and the maintenance of neuropathic pain include the link between neurons and nonneuronal immunocompetent cells (mast cells and microglia) with a cascade of pro- and anti-inflammatory cytokines: this concept introduces an important innovation in pain management. Palmitoylethanolamide (PEA) is a member of the N-acylethanolamine family of fatty acid amide signaling molecules, with antiallodynic and antihyperalgesic properties. PEA acts by downmodulating pro-inflammatory mediator release from mast cells and reducing mast cell and microglial cell activation [44]. At the molecular level, PEA is a peroxisome proliferator-activated receptor alpha (PPAR-α) ligand that performs anti-inflammatory, analgesic, and neuroprotective actions [45]. Few clinical studies demonstrated the efficacy and tolerability of ultramicronized PEA (um-PEA) in the treatment of multiple syndromes associated with chronic pain, poorly responsive to conventional pharmacological regimens, as add-on therapy [46]. Actually, no data are present regarding the use of PEA in CPP.
