Introduction
Research into pain and pain management has long debated the relationship symptom-mechanism-treatment. Newly proposed screening questionnaires, and diagnostic procedures such as quantitative sensory testing, pain-related evoked potentials, and skin biopsy [
19,
33], have advanced the mechanistic approach to pain management leading to the development of the so-called sensory profiles [
6,
9,
20,
59].
Making a specific diagnosis, understanding the underlying pathophysiological mechanism and implementing the proper treatment strategy depends first of all on clearly defining the various types of pain.
In this partly systematic but largely argumentative review, we sought epidemiological and pharmacological studies on MS-related pain. Seeking support for our proposed mechanism-based classification for MS-related pain, we then reviewed studies that help to define and understand the various types of MS-related pain. From current knowledge, our own clinical experience, and information gained from our review, we then tried to classify the different types of MS-related pain according to the underlying pathophysiological mechanism.
We distinguish five pain categories, nociceptive, neuropathic, psychogenic, idiopathic, and mixed. These categories are variably established in the literature. A PubMed search including papers published from inception date to 2011 showed how many articles used these terms:
-
neuropathic pain: 7,759,
-
nociceptive pain (378) or inflammatory pain (1,868); total: 2,246,
-
psychogenic pain (171) or somatoform pain (136) or pain behavior (244); total: 551,
-
idiopathic pain: 74,
-
mixed pain: 46.
To sharpen the distinction between nociceptive pain (whether inflammatory or non-inflammatory), namely pain resulting from nociceptor activation by true or potentially tissue-damaging stimuli, and neuropathic pain, the International Association for the Study of Pain (IASP) has redefined neuropathic pain as pain arising directly from a lesion or disease affecting the somatosensory system [
105]. The previous definition (pain initiated or caused by a primary nervous system lesion or dysfunction) left room for numerous conditions that are neither really or wholly neuropathic. For example, the word
dysfunction allowed inclusion of pain related to secondary functional and neuroplastic changes in the nervous system resulting from sufficiently strong nociceptive stimulation, e.g., central sensitization [
14,
106]. The phrasing
initiated by a primary lesion in
the nervous system left room for any pain in neurological disease, in particular all musculoskeletal pains secondary to movement disorders [
26,
73,
91], a major problem in patients with MS.
Among the five categories of pain, one that is difficult to define is psychogenic pain. This term refers to both primary psychiatric conditions such us somatoform pains associated with anxiety and depression [
30,
36,
47,
53,
84], and also to the superimposed psychogenic components that often develop in patients with chronic refractory pain. This possibility is important to remember because patients with chronic pain may develop a psychogenic component that overwhelms the original organic disease and lose compliance to the theoretically correct therapy (a condition also called
pain behavior) [
99,
108].
The category idiopathic pain encompasses several poorly understood or controversially interpreted chronic pain conditions, including fibromyalgia, irritable bowel syndrome, interstitial cystitis, and persistent idiopathic facial pain [
24,
93], all of which may share a common genetic predisposition or be related to some kind of brain dysfunction [
51,
67,
96]. Because countless patients experience idiopathic pain, the field attracts major research efforts.
The term mixed pain is the least used and the concept remains controversial [
8,
87]. Indeed, many pain clinicians and investigators deny its usefulness, arguing that the term “mixed” adds nothing to “coexisting”. Because many patients may experience more than one type of pain and may have two or more diseases, we need to clarify the difference between “coexisting” and “mixed”.
Coexisting pains are unrelated: their causes and pathophysiological mechanisms differ and they require independent treatment. For instance, in a patient with syringomyelia involving the C5 dermatome who also has a periarthritis shoulder, two independent conditions that just happen to share a similar territory exist and must be independently managed. A more intriguing example comes from a patient with trigeminal neuralgia affecting the mandibular division who has a coexisting temporomandibular disorder. This patient may report the typical electric shock-like attacks of trigeminal neuralgia and a dull, deep, and ongoing pain in the same territory and must therefore be distinguished from a patient with atypical trigeminal neuralgia, a neuropathic pain that entails both paroxysmal and background pain [
70]. Neither patient has mixed pain.
Conversely, in mixed pain, the
same disease causes different pains through different pathophysiological mechanisms that are often difficult to separate and quantify and may therefore raise management problems. A frequent condition that fits this definition is low back pain with sciatica, including both nociceptive components arising from muscles, ligaments, and joints, and neuropathic component arising from the spinal root. When the involved spinal roots innervate proximal territories the neuropathic and nociceptive components may be difficult to separate. Besides spinal root compression, inflammatory mediators originating from the degenerative disc may induce radicular pain without any mechanical compression or nociceptive sprouts within the degenerated disc may give rise to local neuropathic pain [
27]. An important example of mixed pain comes from cancer pain. When lung cancer invades the brachial plexus and the patient feels pain projected to the hand, neuropathic pain clearly adds to nociceptive pain. Emerging evidence, however, suggests that cancer is bound to produce mixed pain with a less obvious mechanism and less clear symptoms: the tumor invading the surrounding tissues destroys the local nerve endings thus inducing regenerating sprouts that are rich in a variety of pain-related channels and also induce central sensitization; so far, this has been well established for bone cancer [
49,
62,
76,
117]. In this case, it is impossible to distinguish between and quantify the nociceptive and neuropathic components.
For multiple sclerosis, the concept of mixed pain is especially important because two types of MS-related pain should be considered mixed: tonic painful spasms and spasticity pain (see below).
Pain in multiple sclerosis: inadequacy of epidemiological studies
Pain is a major burden for patients with MS [
4,
71,
81]. The estimated prevalence of MS-related pain ranges widely from 26 to 86 % [
69,
71]. The high variability reflects differences in the criteria used to define the various types of MS-related pain, the types of pain assessed in the epidemiological survey, the study sample (e.g., population cohorts, hospitalized patients), and the research methods (mail surveys, administrative database queries, and in-person history and examination) [
71]. In a systematic review of pain related to MS, O’Connor and colleagues [
71] found that most studies reported a prevalence higher than 50 %. In a meta-analysis (restricted to studies that provided sufficient information and sufficient quality of methodology), they calculated that 633/854 (74 %) outpatients had pain within 1 month [
71].
The discrepancy in study design and methods accounts also for differences in the reported risk factors for the development of pain related to MS (patient’s age, duration of disease, disease course, and disability). Whereas some studies reported an association between one or more of these factors and pain [
34,
97], others did not [
10,
44,
73]. A large sample study on the prevalence of pain in MS [
97] identified as the main factors associated with the development of pain a longer duration of disease, older age, a non-relapsing-remitting MS course and greater disability. A possible drawback of this finding is that all these factors are intermingled and the study lacked a multivariate analysis to distinguish the role of single factors. The role of the various risk factors in the development of pain therefore awaits clearer answers.
Pain in multiple sclerosis: insufficiency of pharmacological trials
A search of the electronic literature from date of inception to April 2012 showed that only 12 randomized placebo-controlled trials (RCTs) have assessed pharmacological—non disease-modifying—treatment of pain in MS (see “
Appendix” for details about this search). For comparison with MS, we chose diabetic painful neuropathy, because the prevalence of pain in diabetes has been reliably assessed (most studies agree on values between 16 and 19 %) [
22,
23] and is far lower than the estimated prevalence of pain in MS (74 %). Nevertheless, when we surveyed the literature, we found 188 RCTs assessing pain in diabetic neuropathy but only 12 assessing pain in MS. Articles on diabetes are arguably far more numerous than those on MS and drug companies tend to prefer a huge market such as that provided by diabetes. Another reason, however, for the dearth of drug trials is that until a few years ago, most physicians tended to underestimate the importance of pain in MS [
71,
103,
107]. Indeed, when we compared RCTs investigating spasticity and pain in MS, we found that a considerably larger number assessed spasticity than pain (33 vs. 12) and several of the latter were RCTs targeting spasticity that also included pain relief as one of the outcome variables (Table
1).
Table 1
Double-blind placebo-controlled RCTs for pain treatment in multiple sclerosis
Besides the scarcity of RCTs assessing pain related to MS, our review identified other problems. Of the 12 RCTs reviewed, we found only four dedicated to pain assessment [
13,
86,
88], whereas all the others included some pain measure as an item in quality-of-life scales or spasticity scales, and even more importantly, five studies failed to describe the type of pain [
15,
54,
75,
94,
113], and only one generically mentioned “central pain”, without specifying further or distinguishing paroxysmal pain (such as trigeminal neuralgia) from ongoing pain (such as extremity pain) [
13]. Of these six trials, only one, testing dextromethorphan/quinidine, was unambiguously successful in relieving pain [
75].
One study investigated ongoing extremity pain [
88], one ongoing extremity pain and a few patients with painful tonic spasms [
86], one central pain, but specifying that most patients had extremity pain [
100], and three others assessed pain related to spasticity and spasms [
21,
39,
116]. Of these six trials, only one, using botulinum toxin injections, was unsuccessful in relieving pain [
39]. Although the success of a trial depends strongly on the active treatment, among all the trials testing cannabinoids, the only one reporting no significant pain relief was the one that failed to take into account the type of pain [
113]. Our finding that the frequency of success differs significantly (
p = 0.02; Chi-square) between studies that adequately categorized the type of pain and those that did not (Table
1) confirms that pain mechanisms do differ and pharmacological trials should aim to target specific types of pain.
Finally, whereas many trials assessed cannabis derivates, no RCT exists on the drugs that have for long been most popular in treating neuropathic pain (amitriptyline and carbamazepine) or are currently popular (pregabalin and serotonin noradrenaline reuptake inhibitors) [
7,
102].
Conflicts of interest
Although in this review pharmacological trials are compared for methodology rather than drug efficacy, the authors wish to declare that they received honoraria or participated in trials sponsored by the following drug companies: AT: Ely Lilly, Pfizer; PB: Almirall, Lusofarmaco, Merck; CP: Almirall, GW Pharma; GC: Astellas, Ely Lilly, Pfizer.