- Open Access
Pain and psychiatry: a critical analysis and pharmacological review
© Marazziti et al; licensee BioMed Central Ltd. 2006
- Received: 11 September 2006
- Accepted: 06 November 2006
- Published: 06 November 2006
Pain is one of the most difficult medical problems to diagnose and treat and can be a common symptom of several psychiatric disorders. Pain-related issues are heterogeneous and often underestimated or misinterpreted, with the result that psychiatric interventions, which might have been beneficial from the outset, are often delayed or requested only as a last measure. Several problems arise from the definition, classification and assessment of pain, when documented according to the different scales which are commonly used, since these attempt to cover a multitude of analytical requirements, without really succeeding. An area of constant debate regards the connection between pain and various psychiatric disorders, and the difficulty in the classification of pain disorders within the currently existing framework. The pharmacological treatment of pain is complex and implies a variety of different compounds, from opioids to psychotropic medications like antidepressants and anticonvulsivants.
This paper explores the mutual and reciprocal influence between pain and psychiatric disorders reviewing the latest developments in the definition, assessment and treatment of pain, with special emphasis on the impact of pain on psychiatric disorders (and vice versa), and on the use of psychotropic drugs in the treatment of pain syndromes.
- Chronic Pain
- Neuropathic Pain
- Panic Disorder
- Trigeminal Neuralgia
Pain: definition, epidemiology and classification
Pain is a complex experience which includes affective, cognitive and behavioural features, all of which are the result of mental processes and, as such, it represents a psychological condition . The phenomenon of pain, therefore, involves pathophysiological and psychological components that are frequently difficult to interpret. Suffering is a term frequently used in conjunction with pain, implying the conscious endurance of pain or distress and refering to a wide range of intense and unpleasant subjective states that may be of physical or psychologic origin.
The most comprehensive and exhaustive definition of pain is the one provided by the International Association for the Study of Pain, namely "an unpleasant sensation and an emotional experience associated with a real or potential damage to tissue, or the equivalent of such damage". This definition attempts to overcome the dualism between pain provoked by an evident organic disease and that related to psychological factors, that is, between "real" and "imagined" pain, since clearly in either case, the patient's suffering is real.
Pain is a common problem in the general population and is one of the most frequent factors leading patients to consult a physician [3, 4]. When patients suffer from chronic pain – defined as daily pain which has persisted beyond a month or beyond what would normally be considered the appropriate time for recovery from the underlying pathology in question – various specialists are involved in their treatment, but they rarely include a psychiatrist [5–11]. The U.S. Centre for Health Statistics carried out an 8-year follow-up study, which showed that 32.8% of the U.S. civilian population suffered from symptoms related to chronic pain . A recent study carried out by the World Health Organization, which involved more than 25.000 patients in 14 different countries, reported that the 22% of primary care patients had suffered from pain which had been present for most of the time throughout a period of at least 6 months . A review of elderly populations [14, 15] shows that the percentage of individuals affected by some kind of pain rises to 50%, and that this is associated with a significant impairment of social functioning and quality of life; furthermore, about one third of chronic pain cases in elderly people are not recognized by their caregivers [16–19].
In spite of its relevance, pain has long been neglected by the past editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM).
Pain "determined" by emotional factors had been classified within the DSM-II amongst psychophysiological disorders . The DSM-III coped with the problem of chronic pain while introducing the concept of psychogenic pain disorder, where the pathophysiological aspects were absent or insufficient to explain the length and the severity of pain . For somatoform pain disorder (DSM-III), psychological factors were no longer required in pain etiology .
In the revision of the third edition of the DSM-III (DSM-IIIR), specifications requiring psychological factors to be present, and that the pain should not be due to another mental disorder, were deleted and, instead of considering pain itself, the presence of "pain related problems of at least 6 months' duration" was introduced as the main criterion. In line with these changes, the disorder was defined as "somatoform pain disorder". The literature available indicates that the categories of disorders characterized by pain in DSM-III and DSM-IIIR were rarely used for the diagnosis of patients affected by pain . The evident limitations of the diagnosis of psychogenic and somatoform pain led to the introduction of a new diagnostic group more widely defined in the DSM-IV as "pain disorder".
The DSM-IV introduced this category to better define the diagnostic subgroup of somatoform disorders present in the DSM-III-R, which includes also conversion disorder, hysteria and body dysmorphic disorder, all characterized by the common feature of the presence of a physical symptom, which is suggestive of a medical disorder but has not been provoked by it or by substance use [24, 25]. Primary criteria for the diagnosis of pain disorder include 1) pain as the main problem and 2) pain determining significant stress or functional impairment. This diagnosis requires also that although psychological factors may play an important role, the pain must not be the result of another mental disorder, such as an anxiety disorder or depression. Thus, if the presence of another mental disorder is determined, then a diagnosis of pain disorder is not acceptable. Furthermore, it is required that the pain being suffered be defined as acute or chronic and whether associated only with psychological factors or with both psychological factors and a general medical condition. Therefore, the concept of psychological and physical dualism is innate within such a diagnosis.
By definition, a specific medical cause underlying the various somatoform disorders is rarely present ; however, in parallel with the increase in "psychogenic" symptoms, functional or social impairments may arise, there may be an increase in medical treatments, inadequate therapeutic strategies or diagnostic examinations, and psychiatric disorders may appear [26, 27]. These patients have a higher likelihood of reporting catastrophic thoughts and they tend to think that the origin of their pain is a mystery; they feel that they have lost control and that their physicians do not believe their pain to be real. Patients suffering from chronic pain and presenting symptoms with no medical explanation, suffer also from the iatrogenic consequences of their symptoms, such as an excessive number of medical evaluations and long-term treatments with inadequate drugs . Although the diagnosis of somatization disorder is rare in patients with chronic pain, somatization is a common occurrence in medical practice and it may arise with different degrees of severity and be seen in several forms . Somatization may be conceptualized by three distinct, albeit overlapping, models of behavior, according to which "symptoms may be perceived, evaluated and managed differently by different kinds of persons". These three forms include 1) a high level of symptoms which cannot be explained by physiological systems; 2) somatic pathology, related to worries, which is more severe than would normally be expected under the circumstances (as far as can be determined), and 3) the predominantly or exclusively somatic presentation of symptoms of psychiatric disorders, such as depression and anxiety [30–32]. Environmental factors such as the social stigma of psychiatric disorders, a history of physical or sexual abuse and the medical attention given to biochemical paradigms, predispose and reinforce somatization [33–35].
Other classification systems have been proposed, but none is widely applied: the most comprehensive is that developed by the taxonomy sub-committee of the International Association for the Study of Pain  which has set up a model based on 5 axes. Psychological factors may be indicated on both the second axis, where psychiatric disorders may be codified within the central nervous system, and on the fifth axis, where psychophysiological or psychological etiologies may be included.
More controversial, however, is the nosological position of chronic pain syndrome, which is not included anywhere, although this term is frequently used for those individuals suffering from pain for long periods. Black's definition , the most widely accepted, applies the following criteria: untreatable and often multiple areas of pain, usually unrelated to any existing somatic problems, previous contacts with various physicians and diagnostic procedures, excessive worry related to the pain and altered behavior including depressive, anxious or neurotic features. However, the validity of this diagnosis is limited because some of the above-mentioned criteria are highly subjective and repeated diagnostic tests might have been due to low awareness of the pain on the part of the physician. For these reasons, the diagnosis of chronic pain syndrome, according to some authors, should be avoided .
Different theories have been proposed in this field and, although none is considered exhaustive, the most accepted is the gate control hypothesis . It postulates that the transmission of nerve impulses from the periphery through the central nervous system (CNS) is modulated by T-cells in the substantia gelatinosa of the dorsal horn of the spinal cord, which are influenced by different inputs. These include large inhibitory and small facilitating fibres from the brain, the level of arousal via the reticular activating system and autonomic modulation via the sympathetic ganglia. This theory has considerable heuristic merit and provides a rationale by which emotions or experience could affect pain. A variety of biochemical mechanisms also modulate pain. Analgesia is enhanced by increased levels of serotonin in the periacqueductal grey matter or by potentiating inhibitory substance P in the spinal cord; the opposite may result from the blockade of dopamine or increase of norepinephrine in the lateral reticular formation. These mechanisms indicate the potential effects of biogenic amines and psychotropic drugs on pain, which probably have a modulating but less specific function than brain opiate receptors and the endogenous or exogenous substances acting at their level in both the limbic system and the substantia gelatinosa .
It is sometimes difficult to evaluate pain, especially in patients with a terminal disease, with cognitive impairments or other chronic degenerative neurological disorders [9, 10]. Different pain rating scales are available to assess the severity and the intensity of pain, but several factors may influence these evaluations, in particular the somatic conditions, the co-occurrence of psychiatric disorders, the presence of stress, the personality characteristics and an interpretation based on subjective experience.
A complete evaluation should be carried out with every patient suffering from pain or agitation or with an evident worsening of his/her functional status. This evaluation should take into consideration simple standardized items to measure the severity of pain, the observation of any pain-associated behavior such as difficulty with daily life activities as a result of pain and a clinical examination in order to localize the pain and any signs which might suggest possible etiological agents.
The simplest measurement of pain is the Numeral Evaluation Scale, where the patient is asked to assign a number to the pain suffered. The typical scale has a range of 0 to 10, with "0" representing a total absence of pain and "10" the worst imaginable pain. Strongly related to this is the visual analogical scale that requires the subject to indicate a point along a line of 10 cm, where 0 is no pain and 10 is the worst .
The McGill Pain Questionnaire offers a more accurate analysis , with the test listing 20 series of words describing the pain and assigned to sensorial, affective and rating scales. The test score may be defined on the basis of the total number of words chosen or by the order in which they are expressed. Some studies, however, indicate that the modality of response varies according to the kind of pain ; the McGill Pain Questionnaire has been criticized because it is based excessively on linguistic abilities, and consequently, its results may be influenced by the degree of individual intelligence or education.
An alternative test commonly used is the West Heaven-Yale Multidimentional Inventory, composed of 52 items which measure the way in which patients perceive other people's reaction to their pain, participation in everyday life and the effect that the pain is having on their global lifestyle .
Other more traditional psychological evaluation tests have also been used, such as the Minnesota Multiphasic Personality Inventory (MMPI); nevertheless, the validity of this and other similar tests is controversial when applied to subjects with pain. For instance, it has been reported that more than 40 years ago, individuals with back pain whose origin was not organic, were more likely to present a certain MMPI configuration, the so called "V of conversion" or "neurotic triad", where it was believed that an increase in hypochondria and hysteria scale reflected patients' worries about their own health , while a lower score of depression indicated that the patient was indifferent to such worries. Despite the existence of supporting data, other studies would suggest that this specific configuration may represent a sort of adaptation to a chronic disorder and, consequently, it may be a characteristic of patients with chronic health problems, independently of any identified organic etiology [46, 47].
To assist caregivers in distinguishing whether a patient's pain had an organic or a psychological origin, Waddel and co-workers  suggested the noting of 5 possible signs: 1) pain which is superficial or without anatomic distribution; 2) pain which is induced by any movement which should not be painful but which might appear similar to some other movement which normally would be; 3) pain which seems to vanish when the subject is distracted; 4) focal disturbances, such as hypostenia or sensorial deficit, without anatomic distribution; 5) a patient's hyper-reaction during clinical examination.
Since the accurate evaluation of pain is controversial and possibly influenced by a large number of factors, it might be useful to introduce the concept of "behavior in pathology" [30, 49], which could include considerations such as the perception of pain, any decision regarding treatment and the person responsible for this decision, the meaning of pain for the patient and the way the patient talks about the pain and its effect on his/her functioning. The cultural background, the socio-economical conditions, the psychological functioning, the experiences, memory and learning are some of the factors which may influence behavior in pathology. Although the concept of behavior in pathology has been applied more frequently to chronic pain, several observations indicate that some of these factors play a significant role also in acute pain. In a pioneering study, Beecher  observed that soldiers who were very severely wounded in battle often did not refer to pain or if they did, it was often to a much lesser extent than might have been expected, given the severity of the wound in question. The author hypothesized that this might reflect the relief of soldiers who had realized that now that they were wounded they would be removed from the field of battle and that their life would no longer be at risk; on the other hand, life stressors might contribute to the development of chronic pain .
It has also been demonstrated that a person's knowledge and expectation of potential pain can modify his/her response. Egbert and co-workers  found that the pre-operatory psychological preparation of the patient had a significant influence on post-surgical recovery as well as the amount of pain felt. Other studies indicated the existence of significant differences between cultures and ethnic groups with regard to how persons report pain and their response to it. In pathology, the kind of behavior which is generally considered acceptable varies from culture to culture. Zborowski  studied experiences of pain amongst "old-Americans" (i.e. of Anglo-Saxon origin), Italo-Americans and American Jews and he observed that the "old-Americans" were generally stronger and had a greater tendency to avoid social contact when experiencing pain, compared with the others. Similarly, Sternbach and Tursky  compared different ethnic groups and found that there were differences in the tolerance of pain between the groups and this was subsequently reported also by other authors [55–57].
Although there is unquestionably some connection between pain and various psychiatric disorders, its exact nature is a matter of debate. The majority of studies on this topic have focused on the frequency of psychiatric disorders amongst patients reporting pain, but a few studies investigating pain in psychiatric subjects have reported this as a common problem. Deplaine and coauthors  found that 38% of 227 psychiatric inpatients reported pain; Chaturvedi  identified pain symptoms in 18% of patients in a psychiatric department. Both studies underlined that pain was more frequent amongst patients affected by neurosis, as compared with those suffering from schizophrenia or psychotic disorders. Chronic pain would seem to be associated most frequently with a variety of depressive disorders such as major depression, dysthymia and adaptation disorder with depressive mood. The available literature reports a variability in the prevalence of chronic pain ranging from 10 to 100% [60, 61]. The heterogeneous results may reflect the difficulty in applying this diagnosis to patients with pain, but may also be related to differences in the evaluated populations. These disorders have been identified in patients with an evident organic etiology for pain as well as in subjects without it, although the disorders would seem to be more common in the latter group .
Although some patients have been hypothesized as developing pain as a response to depressive symptoms, other viewpoints have been put forward. According to Engel , there may be individuals who, as a result of specific psychological factors, may be considered "prone to pain". Similarly, Blumer and Heilbronn  hypothesized that associated mental disorders might precede and/or create a predisposition towards pain and they described an individual prone to pain, for whom it represents a form of masked depression. Some studies indicate that depressive disorders and alcohol dependence are more common in first-degree relatives of patients with chronic pain, thus suggesting a possible environmental or biological predisposition to the development of pain [32, 62, 65–67]. Other studies would suggest that depression is secondary to pain [31, 68], or that both problems can coexist independently or as a result of a common psychological or neurochemical background [62, 69, 70].
Even some forms of acute pain appear to be associated frequently with other mental disorders; Beithman and co-authors  observed that more than 30% of patients with chest pain and normal coronary circulation assessed by means of coronarography met the criteria for panic disorder.
The National Health and Nutrition Study underlined that depression was more frequent in older patients, irrespective of the presence of any pain ; nevertheless, the relationship between pain and depression is still controversial . Approximately 60% of patients with depression present pain at the moment of the diagnosis [74, 75]. The presence of depressive disorder may increase the risk of developing a musculoskeletal pain, headache and chest pain 3 years later on [12, 76–78]. Elderly patients with depression are at increased risk for cervical, lumbar and hip pain. Even after 8 years, patients with a previous depression still had a double risk of developing chronic pain, as compared with non-depressed patients.
Depression prevalence was 12% in individuals with three or more pain-related symptoms, as compared with 1% of patients without pain or one only pain-related symptom, amongst 1016 subjects . Major depression prevalence in patients with chronic lumbar pain was three times higher than in the general population . In groups of patients with symptoms with no medical explanation, such as lumbar pain or dizziness, two thirds had a history of recurrent major depression compared with less than 20% in the control group with medical disorders [31, 81, 82]. In patients with chronic pain included in a program of pain evaluation, between 8% and 50% had suffered from major depression . Where pain led to a loss of independence or motricity with impairment of social functioning, the risk of depression increased significantly . Individuals with chronic problems are at a higher risk of developing lifetime depression and it hasbeen hypothesized that this may be the case with particularly vulnerable individuals.
Depression is not simply a comorbid condition when associated with chronic pain, since it interacts by increasing morbility and mortality. Patients with chronic pain and depression have reported major pain, a reduction in control over life events and a higher probability of coping with stress by adopting passive strategies . They have reported also that this interfered with their lives and they exhibited pain-related behaviors more frequently than did those patients with chronic pain but without depression [85, 86]. The presence of pre-operatory depression in patients who underwent lumbar disc surgery was a predictor of a worse result during a 1-year follow-up . In patients with rheumatoid arthritis, depressive symptoms were significantly associated with negative functional results and with a greater utilization of health services . Depression may be a significant predicting factor of pain persistence and of anticipated retirement [12, 89]. However, the measurement of pain threshold, by means of different techniques, has led to controversial findings .
Patients with headache, chronic abdominal pain and painful orthopaedic syndromes have reported a higher level of suicide thoughts and attempts than those without . In those patients reporting a suicide attempt, 25% suffered from a somatic disease and 21% took pain relievers daily for the pain . Patients with chronic pain are at two to three times greater risk of a completed suicide than the general population . Oncological patients with pain and depression showed a higher likelihood of committing suicide, by searching for information regarding the possibility of suicide or withdrawal from treatment; however, if affected by pain but without depression, they did not request euthanasia or assisted suicide , therefore depression must be treated correctly and not simply "understood" as the unavoidable result of chronic pain.
Patients with different painful syndromes, such as chronic lumbar pain, chronic cervical pain following whiplash or chronic pain due to prostatic cancer, showed an increased risk of anxiety syndromes or disorders [94–97]. At least 50% of patients show anxiety symptoms and 19% have an anxiety disorder such as panic disorder or generalized anxiety disorder [32, 98, 99].
A prospective study involving 1007 young adults found that a history of headache was associated with a higher risk (odds ratio = 12.8) of panic disorder . On the other hand, anxiety disorders are associated with high somatic preoccupation levels and physical symptoms. In a study of patients with panic disorder, at least 40% described chronic pain symptoms and more than 7% took pain relievers daily . When compared with other patients with panic disorder, this sub-group had a higher frequency of abnormal behaviors related to the disease. The self-evaluation of pain intensity in patients with rheumatoid arthritis was significantly influenced by the presence of anxiety and depression, even when the factor related to the activity of the main disease was controlled .
Terms such as addiction, misuse, excessive use and abuse are usually applied inconsistently to describe different behaviors and they may complicate the interpretation of several studies. Frequently the use of drugs is not reported completely and this impairs the accurate evaluation of their use when made by patients with chronic pain ; in patients with chronic pain who develop an addiction to new substances, usually this derives from drugs prescribed by the physician [104, 105]. The mechanism underlying the relapse of substance abuse amongst these patients is not well-known and it is based upon several factors; however, a period of pain followed by a remission after the use of drugs constitutes a typical example of a situation likely to lead to their use in the future . In a study performed in a group of outpatients consulting a centre specialized in the treatment of pain, almost 90% were taking drugs , opioids were prescribed in 70% of the cases, while antidepressants and benzodiazepines were taken by 25% and 18% of the patients, respectively. Amongst this population, 8% met DSM-III-R criteria for substance abuse or addiction; however, misuse and drug abuse were not limited to psychoactive substances. In a review of 24 studies on drug and alcohol dependence in patients with chronic pain, only 7 met the standard criteria for substance abuse disorders, and the prevalence ranged from 3.2% to 18.9% . In a study carried out in patients with chronic lumbar pain, 34% had a substance abuse disorder, which in all cases had already been present before the onset of pain . Individuals with a history of substance abuse ran a major risk of resuming substance abuse while suffering from chronic pain, and also of suffering further physical damage .
Research related to substance abuse has revealed abnormalities in the perception and tolerance of pain. In a study carried out in patients with cocaine and opioid abuse, tolerance of the cold pressor test was significantly lower amongst those who were still indulging in substance abuse, than amongst those who were no longer doing so . Alcoholic patients and non-alcoholic males with a high genetic risk of alcoholism, have a higher sensitivity than control subjects to painful stimuli, but this difference in sensitivity was reduced by the intake of pharmacological doses of alcohol . This increase in sensitivity and the relief due to substance abuse would suggest a possible explanation of substance abuse in patients with chronic pain.
This review will focus mainly on pharmacological strategies with special attention being paid to the use of psychotropic compounds. However, apart from pharmacological agents, there exist several heterogeneous techniques for the treatment of pain, such as surgical intervention, nerve blocking, physiotherapy, acupuncture or electrical stimulation, just to mention a few. Among psychotherapies, moreover, cognitive-behavioral therapies (CBT) are considered effective treatments for a variety of pain problems [112–114]. A discussion of these techniques would go beyond the scope of this paper and could be found elsewhere .
The use of opiates for non-malignant chronic pain is a matter of debate . For a long time, opiates were reserved for the treatment of painful syndromes related to cancer or to those of acute pain; however, different studies aimed at assessing the risk of abuse have provided reassuring results, in particular that carried out in a group of more than 12000 patients with medical disorders who had been treated with opiates, which showed that, of those without a past history of abuse, only 4 developed drug dependence [117, 118]. Open-label and controlled trials support the safety and the efficacy of opiates in the treatment of non-malignant chronic pain.
The most common side-effect following chronic use is the reduction of gastro-intestinal motility, with consequent constipation . However, the main reason why these drugs are not widely prescribed is that there is concern regarding possible cognitive impairment. Such literature as is available has reviewed only some of the effects shown by neuro-psychological tests or electroncephalogram modifications in patients taking combinations of drugs, mainly sedatives and hypnotics [120–123]. When the opiate treatment is not effective, the drug should be suspended gradually in order to decrease withdrawal symptoms. The opiate withdrawal is usually dangerous only in those patients at risk with regard to an increase in the sympathetic tone, that is, for instance, in those who show an increase in intracranial pressure or unstable angina. In any event, however, it should be borne in mind that opiate reduction usually leads to a return of the original painful symptoms (rebound pain).
After the first study reporting the effectiveness of imipramine in the treatment of trigeminal neuralgia , antidepressants, especially tricyclics (TCAs), have frequently been prescribed for the treatment of several chronic painful syndromes, but mainly for neuropathic pain. Various different studies have suggested that the antidepressant effects on pain are mediated by the blockade of the norepinephrine and serotonin re-uptake which increases neurotransmitter levels and, therefore, potentiates the activation of the descendent inhibitory pathways [62, 125]. Other aspects of monoaminergic systems are involved in the analgesic action of antidepressants, for example, β-adrenergic receptors may mediate the analgesic effects of desipramine and nortriptyline . In general, amitriptyline, or TCAs with a similar pharmacological profile, are considered the most effective drugs; however, randomized controlled clinical trials have not demonstrated the existence of any significant differences between TCAs . In a review of 39 controlled studies versus placebo, in 80% of the cases, antidepressants proved superior to the placebo . TCAs have been the most effective drugs for pain remission in neuropathic pain and headache, and the analgesic activity would seem to be independent of any effect on mood [129–134]. A recent controlled randomized study of nortriptyline versus placebo in patients with chronic lumbar pain without depression, showed a significant reduction in the scores related to pain intensity . The results of studies which have assessed the plasma levels of drugs necessary for pain remission are still controversial and clear guidelines have not been established as yet . Nortriptyline, the main amitriptyline metabolite, induces less sedation and less orthostatic hypotension than imipramine, but has an analgesic potency comparable to that of amitriptyline [137, 138]. The cost of pain treatment with TCAs is usually much lower than that with other antidepressants or drugs with an analgesic action, such as β-blockers or calcium-antagonists . Selective serotonin re-uptake inhibitors (SSRIs) have a weak antinociceptive action in animal models of acute pain [140–142]. Several studies have investigated the role of different serotonin receptor subtypes in the mechanisms of pain, but they are very controversial [143–145]. SSRIs do not seem to be as effective as TCAs for chronic pain; for instance, desipramine is superior to fluoxetine in the treatment of painful peripheral diabetic neuropathia . Recently these drugs have been shown to be effective and well-tolerated in the treatment of headache, in particular of migraine [147, 148]. The role of biogenic amine in the descendent inhibition of pain would suggest the potential efficacy of all antidepressants, whatever their mechanism of action . In studies of thermic nociception, the norepinephrine re-uptake inhibitors, such as reboxetine, and the dopamine re-uptake inhibitors, such as bupropion, may produce an antinociceptive effect . Trazodone has been effective in reducing pain in a double-blind controlled study carried out in patients with chronic lumbar pain [151, 152]. In an animal model of neuropathic pain, venlafaxine, a compound inhibiting both the re-uptake of norepinephrine and serotonin (SNRI), was shown to prevent the development of hyperalgesia . Of note, duloxetine, a balanced SNRI, has been recently considered a new treatment option for patients with neuropathic pain after showing promising results in controlled trials .
Anticonvulsants are considered the most effective drugs in the treatment of trigeminal neuralgia, of diabetic neuropathy, and of migraine recurrence . Phentoine was the first drug found to be effective in the treatment of trigeminal neuralgia in 1942 . Carbamazepine is the most studied anticonvulsant which has proven to be effective in the treatment of neuropathic pain . However, anticonvulsants have different pharmacological actions which may have a role in analgesia with potentially useful connections with a series of chronic pain syndromes. Several anticonvulsants block the activity of sodium channels and, therefore, would stabilize the pre-synaptic neuronal membrane, decrease the release of excitatory neurotransmitters and reduce the spontaneous firing of damaged or recovering nociceptive fibres. Phentoine regulates many aspects of nervous functioning, such as the activity of ATPase, synaptic transmission, the release of neurotransmitters and ion conduction . Carbamazepine reduces the tryptophan concentration binding plasma proteins and consequently increases serotonin levels in rat brain . The use of carbamazepine, however, is restricted by unwanted side-effects such as sedation, ataxia and plastic anemia. Therapeutic plasma levels have not been defined clearly, but there is evidence to suggest that low levels may be effective in reducing pain .
New classes of anticonvulsants have different pharmacological actions which may prove to be analgesic. Valproic acid is more frequently used in migraine prophylaxis but it is effective also in the treatment of neuropathic pain . In a study on migraine, valproate proved to be effective in the prophylactic treatment of more than two thirds of the patients, with minimal side-effects such as nausea, dizziness or tremors . The mechanism of action of valproate is probably related to an increase in GABA levels, mediated by the inhibition of GABA transaminase and the increase of GABA synthesis. Valproate is usually well-tolerated, but it requires regular monitoring because of its potential hepatotoxicity and suppression of bone marrow.
In open-label studies, gabapentin has been shown to reduce pain in multiple sclerosis, migraine, post-herpetic neuralgia (PHN) and reflex sympathetic distrophy [161, 162]. The mechanism of action of gabapentin may be related to the binding to the α2δ subunit of the voltage-dependent calcium channels . Clinical cases exist which suggest that lamotrigine may be effective in reducing phantom limb pain, post-stroke central pain and PHN [164, 165]. The mechanism of action of lamotrigine may result from the reduction in the long-term excitatory effects of glutamatergic nociceptive transmission mediated by NMDA receptors, but it also blocks the voltage-dependent sodium channels [166–168].
Benzodiazepines are frequently prescribed for insomnia and anxiety in patients with chronic pain [169, 170]. In a review of published literature, only a few conditions involving chronic pain, such as trigeminal neuralgia, tensive headache and temporal-mandible joint disorder, seem to improve after treatment with benzodiazepines . It is difficult to assess the positive effects of benzodiazepines, however the negative effects have been studied thoroughly and they amount to more than the usual worries related to abuse, dependence, abstinence or secondary effects on mood. Elderly subjects are particularly sensitive to the side-effects of benzodiazepines, such as sedation [172–176]. Benzodiazepines determine also a cognitive impairment, as demonstrated by the abnormalities of neuropsychological tests and electroencephalograms .
Pain is a common problem in medical practice and it continues to be underestimated and undertreated despite the existence of effective treatments.
The psychological aspects of pain are evident; nevertheless these are rarely assessed or managed as they should be. Furthermore, pain can often represent a non-specific sign or symptom of specific psychiatric disorders, such as depression or anxiety, or it can constitute a disorder in itself, as acknowledged by current psychiatric classification systems and as a result, in most cases, psychiatric intervention can prove beneficial.
- Turk DC, Meichenbaum D, Genest M: Pain and Behavioural Medicine. A Cognitive and Behavioural Perspective. 1983, New York, GuilfordGoogle Scholar
- Merskey H, Lindblom U, Mumford JM, Nathan PW, Noordenbos W, Sunderland SS: Pain terms: a current list with definitions and notes usage. Pain (S3). 1986, S215-S221.Google Scholar
- Kroenke K, Mangelsdorff A: Common symptoms in ambulatory care: incidence, evaluation, therapy and outcome. Am J Med. 1989, 86: 262-266.PubMedGoogle Scholar
- Kroenke K, Arrington ME, Mangelsdorff AD: The prevalence of symptoms in medical outpatients and the adequacy of therapy. Arch Intern Med. 1990, 150: 1685-1689.PubMedGoogle Scholar
- Bonica JJ: Definition and taxonomy of pain, in The Management of Pain. Edited by: Bonica JJ. 1990, Philadephia, PA, Lea & Febiger, 18-27.Google Scholar
- Cleary JF, Carbone PP: Palliative medicine in the elderly. Cancer. 1997, 80: 1335-1347.PubMedGoogle Scholar
- Ferrel BA: Pain management in the elderly people. J Am Geriatr Soc. 1991, 39: 64-73.Google Scholar
- Harkins SW: Geriatric pain. Pain perceptions in the old. Clin Geriatr Med. 1996, 12: 435-459.PubMedGoogle Scholar
- Nikolaus T: Assessment of chronic pain in the elderly patients. Ther Umsh. 1997, 54: 340-344.Google Scholar
- Parmelee PA: Pain in cognitively impaired older persons. Clin Geriatr Med. 1996, 12: 473-487.PubMedGoogle Scholar
- Karlsten R, Gordh T: How do drugs relieve neurogenic pain?. Drugs Aging. 1997, 11: 398-412.PubMedGoogle Scholar
- Magni G, Marchetti M, Moreschi C, Merskey H, Luchini SR: Chronic musculoskeletal pain and depressive symptoms in the National Health and Nutrition Examination, I: epidemiologic follow-up study. Pain. 1993, 53: 163-168.PubMedGoogle Scholar
- Gureje O, Von Korff M, Simon GE, Gater R: Persistent pain and well-being: a World Health Organization study in primary care. JAMA. 1998, 280: 147-151.PubMedGoogle Scholar
- Gagliese L, Melzack R: Chronic pain in elderly people. Pain. 1997, 70: 3-14.PubMedGoogle Scholar
- Gloth RM: Concerns with chronic analgesic therapy in the elderly patients. Am J Med. 1996, 101: 19S-24S.PubMedGoogle Scholar
- Stein WM, Ferrell BA: Pain in the nursing home. Clin Geriatr Med. 1996, 12: 601-613.PubMedGoogle Scholar
- Rani PU, Naidu MU, Prasad VB, Rao TR, Shobha JC: An evaluation of antidepressant in rheumatic pain conditions. Anesth Analg. 1996, 83: 371-375.PubMedGoogle Scholar
- Acute Pain Management Guideline Panel: Acute pain management: operative or medical procedures and trauma. Clinical practice guideline (AHCPR Publ No 92-0032). Rockville, MD, Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. 1992Google Scholar
- Nishikawa ST, Ferrell BA: Pain assessment in the elderly. Clinics in Geriatric Issues in Long Term Care. 1993, 1: 15-28.Google Scholar
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 1968, Washington, DC, American Psychiatric Press, 46-48. 2Google Scholar
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 1980, Washington, DC, American Psychiatric Press, 247-249. 3Google Scholar
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 1987, Washington, DC, American Psychiatric Press, 264-266. 3rd RevisedGoogle Scholar
- King SA, Strain JJ: Somatoform pain disorder, in The DSM-IV. American Psychiatric Association. 1994, Washington DC, American Psychiatric PressGoogle Scholar
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 1994, Washington, DC, American Psychiatric Press, 458-462. 4Google Scholar
- King SA, Stain JJ: Revising the category of somatoform pain disorder. Hospital and Community Psychiatry. 1992, 43: 217-219.PubMedGoogle Scholar
- Brown JW, Robertson LS, Kosa J, Alpert JJ: A study of general practice in Massachusetts. JAMA. 1971, 2216: 301-306.Google Scholar
- Koch HK: The National Ambulatory Medical Care Survey: 1975 Summary (DHHS Publ No PHS 78-1784). 1978, Hyattsville, MD, U.S. Department of Health, Education, and WelfareGoogle Scholar
- Katon W, Lin E, Von Korff M, Russo J, Lipscomb P, Bush T: Somatization: a spectrum of severity. Am J Psychiatry. 1991, 148: 34-40.PubMedGoogle Scholar
- Kouyanou K, Pither CE, Rabe-Hesketh S, Wessely S: A comparative study of iatrogenesis, medication abuse, and psychiatric morbidity in chronic pain patients with and without medically explained symptoms. Pain. 1998, 76: 417-426.PubMedGoogle Scholar
- Mechanic D: The concept of illness behavior. Journal of Chronic Diseases. 1962, 15: 189-194.PubMedGoogle Scholar
- Atkinson JH, Slater MA, Patterson TL, Grant I, Garfin SR: Prevalence, onset and risk of psychiatric disorders in men with chronic low back pain: a controlled study. Pain. 1991, 45: 111-121.PubMedGoogle Scholar
- Katon W, Egan K, Miller D: Chronic pain: lifetime psychiatric diagnoses and family history. Am J Psychiatry. 1985, 142: 1156-1160.PubMedGoogle Scholar
- Kirmayer LJ, Robbins JM: Three forms of somatization in primary care: prevalence, co-occurrence, and sociodemographic characteristics. J Nerv Ment Dis. 1991, 179: 647-655.PubMedGoogle Scholar
- Kroenke K: Somatization in primary care: an inclusive approach to the symptomatic patient. American Pain Society Journal. 1993, 2: 150-153.Google Scholar
- Walling MK, O'Hara MW, Reiter RC, Milburn AK, Lilly G, Vincent SD: Abuse history and chronic pain in women, II a multivariate analysis of abuse and psychological morbidity. Obstet Gynecol. 1994, 84: 200-206.PubMedGoogle Scholar
- Black RG: The chronic pain syndrome. Surg Clin North Am. 1975, 55: 999-1011.PubMedGoogle Scholar
- Melzak R, Wall PD: Pain mechanisms: a new theory. Science. 1965, 150: 971-979.Google Scholar
- Melzak R, Wall PD: The Challenge of Pain. New York, Basic Books. 1983Google Scholar
- Chapman CR, Casey KR, Dubner R, Foley KM, Gracely RH, Reading AE: Pain measurement: an overview. Pain. 1985, 22: 1-31.PubMedGoogle Scholar
- Williams RC: Toward a set of reliable and valid measures for chronic pain assessment and outcome research. Pain. 1988, 35: 239-251.PubMedGoogle Scholar
- Scott J, Huskisson EC: Graphic representation of pain. Pain. 1976, 2: 175-184.PubMedGoogle Scholar
- Melzak R: The McGill Pain Questionnaire: major properties and scoring methods. Pain. 1975, 1: 277-299.Google Scholar
- Reading AE, Everitt BS, Sledmere CM: The McGill Pain Questionnaire: a replication of its construction. Br J Clin Psychol. 1982, 21: 339-349.PubMedGoogle Scholar
- Kerns RD, Turk DC, Rudy TE: The West Heaven-Yale Multidimensional Pain Inventory (WHYMPI). Pain. 1985, 23: 345-356.PubMedGoogle Scholar
- Hanvik LJ: MMPI profiles in patients with low-back pain. J Consult Clin Psychol. 1951, 15: 350-353.Google Scholar
- Naliboff BD, Cohen MJ, Yellen AN: Does the MMPI differentiate chronic illness from chronic pain?. Pain. 1982, 13: 333-341.PubMedGoogle Scholar
- Watson D: Neurotic tendencies among chronic pain patients: an MMPI item analysis. Pain. 1982, 14: 365-385.PubMedGoogle Scholar
- Waddel G, McCulloch JA, Kummel E, Venner RM: Nonorganic physical signs in low-back pain. Spine. 1980, 5: 117-125.Google Scholar
- Pilowsky I: Abnormal illness behavior. Br J Med Psychol. 1969, 42: 347-351.PubMedGoogle Scholar
- Beecher HK: Pain in men wounded in battle. Ann Surg. 1946, 123: 98-105.Google Scholar
- Atkinson JH, Slater MA, Grant I, Patterson TL, Garfin SR: Depressed mood in chronic low back pain: relationship with stressful life events. Pain. 1988, 35: 47-55.PubMedGoogle Scholar
- Egbert LD, Battit GE, Welch CD, Bartlett MK: Reduction of post-operative pain by encouragement and instruction of patients. New Engl J Med. 1964, 270: 825-827.PubMedGoogle Scholar
- Zoborowski M: People in pain. San Francisco. Jossey-Bass. 1969Google Scholar
- Sternbach RA, Tursky B: Ethnic differences among housewives in psychophysical and skin potential response to electric shock. Psychophysiology. 1965, 1: 241-246.PubMedGoogle Scholar
- Pilowsky I, Spence ND: Ethnicity and illness behavior. Psychol Med. 1977, 7: 447-452.PubMedGoogle Scholar
- Moore R: Ethnographic assessment of pain coping perceptions. Psychosom Med. 1990, 52: 171-181.PubMedGoogle Scholar
- Greenwald HP: Interethinc differences in pain perception. Pain. 1991, 44: 157-163.PubMedGoogle Scholar
- Delaplaine R, Ifabumuiy OI, Merskey H, Zarfas J: Significance of pain in psychiatric hospital patients. Pain. 1978, 4: 361-366.PubMedGoogle Scholar
- Chaturvedi SK: Prevalence of chronic pain in psychiatric patients. Pain. 1987, 19: 231-237.Google Scholar
- King SA, Strain JJ: The problem of psychiatric diagnosis for the pain patient in the general hospital. Clin J Pain. 1989, 5: 329-335.PubMedGoogle Scholar
- Romano JM, Turner JA: Chronic pain and depression: does the literature support a relationship?. Psychol Bull. 1985, 97: 18-34.PubMedGoogle Scholar
- Magni G: On the relationship between chronic pain and depression when there is no organic lesion. Pain. 1987, 31: 1-21.PubMedGoogle Scholar
- Engel GL: "Psychogenic" pain and the pain-prone patient. Am J Med. 1959, 26: 899-918.PubMedGoogle Scholar
- Blumer D, Heilbronn M: Chronic pain as a variant of depressive disease: the pain-prone disease. J Nerv Ment Dis. 1982, 170: 381-406.PubMedGoogle Scholar
- Chaturvedi SK: A comparison of depressed and anxious chronic pain patients. Gen Hosp Psychiatry. 1987, 9: 383-386.PubMedGoogle Scholar
- Hudson JI, Hudson MS, Pliner LF, Goldenberg DL, Pope HG: Fibromyalgia and major affective disorder: a controlled phenomenology and family history study. Am J Psychiatry. 1985, 142: 441-446.PubMedGoogle Scholar
- Violon A, Giurgea D: Familiar models for chronic pain. Pain. 1984, 18: 199-203.PubMedGoogle Scholar
- Brown GK: A causal analysis of chronic pain and depression. J Abnorm Psychol. 1990, 99: 127-137.PubMedGoogle Scholar
- Feinmann C: Pain relief by antidepressant: possible models of action. Pain. 1985, 23: 1-8.PubMedGoogle Scholar
- Gamsa A: Is emotional disturbance a precipitator or a consequence of chronic pain?. Pain. 1990, 42: 183-195.PubMedGoogle Scholar
- Beithman BD, Mukerji V, Lamberti JW, Schmid L, DeRosear L, Kushner M, Flaker G, Basha I: Panic disorder in patients with chest pain and angiographically normal coronary arteries. Am J Cardiol. 1989, 63: 1399-1403.Google Scholar
- Harkins SW, Kwentus J, Prince DD: Pain and the elderly, in Advances in Pain Research and Therapy. Edited by: Benedetti C, Chapman CE, Morrica G. 1984, New York, Raven, 7: 103-121.Google Scholar
- Lipowski ZJ: Somatization and depression. Psychosomatics. 1997, 31: 13-21.Google Scholar
- Magni G, Schifano F, DeLeo D: Pain as symptom in elderly depressed patients. Relationship to diagnostic subgroups. Eur Arch Psychiatry Neurol Sci. 1985, 235: 143-145.PubMedGoogle Scholar
- Von Knorrig L, Perris C, Eisemann M, et al: Pain as a symptom in depressive disorders, I: relationship to diagnostic subgroup and depressive symptomatology. Pain. 1983, 15: 19-26.Google Scholar
- Leino P, Magni G: Depressive and distress symptoms as predictors of low back pain, neck-shoulder pain, and other musculoskeletal morbidity: a 10 years follow-up of metal industry employees. Pain. 1993, 53: 89-94.PubMedGoogle Scholar
- Magni G, Moreschi C, Rigatti-Luchini S, Merskey H: Prospective study on the relationship between depressive symptoms and chronic musculoskeletal pain. Pain. 1994, 56: 289-297.PubMedGoogle Scholar
- Von Korff M, LeReshe L, Dworkin SF: First onset of common pain symtoms: a perspective study of depression as a risk factor. Pain. 1993, 55: 251-258.PubMedGoogle Scholar
- Dworkin SF, Von Korff M, LeReshe L: Multiple pains and psychiatric disturbance: an epidemiologic investigation. Arch Gen Psychiatry. 1990, 47: 239-244.PubMedGoogle Scholar
- Sullivan MJ, Reesor K, Mikail S, Fisher R: The treatment of depression in chronic low back pain: review and recommendations. Pain. 1992, 50: 5-13.PubMedGoogle Scholar
- Sullivan M, Katon W: Somatization: the path between distress and somatic symptoms. American Pain Society Journal. 1993, 2: 141-149.Google Scholar
- Katon W, Sullivan M: Depression and chronic medical illness. J Clin Psychiatry. 1990, 150 (S): 3-11.Google Scholar
- Smith GR: The epidemiology and treatment of depression when it coexists with somatoform disorders, somatization, or pain. Gen Hosp Psychiatry. 1992, 14: 265-272.PubMedGoogle Scholar
- Williamson GM, Shulz R: Pain, activity restriction and symptoms of depression among community residing elderly adults. J Gerontol A Biol Sci Med Sci. 1992, 47: 367-372.Google Scholar
- Haythornthwaite JA, Sieber WJ, Kerns RD: Depression and the chronic pain experience. Pain. 1991, 46: 177-184.PubMedGoogle Scholar
- Weickgenant AL, Slater MA, Patterson TL, Atkinson JH, Grant I, Garfin SR: Coping activities in chronic low back pain: relationship with depression. Pain. 1993, 53: 95-103.PubMedGoogle Scholar
- Junge A, Dvorak J, Ahrens S: Predictors of bad and good outcomes of lumbar disc surgery. A prospective clinical study with recommendations for screening to avoid bad outcomes. Spine. 1995, 20: 460-468.PubMedGoogle Scholar
- Katz PP, Yelin EH: Prevalence and correlates of depressive symptoms among persons with rheumatoid arthritis. J Rheumatol. 1993, 20: 790-796.PubMedGoogle Scholar
- Hasenbring M, Marienfeld G, Kuhlendahl D, Soyka D: Risk factors of chronicity in lumbar disc patients. A prospective investigation of biologic, psychologic, and social predictors of therapy outcome. Spine. 1994, 46: 2759-2765.Google Scholar
- Magni G, Rigatti-Luchini S, Fracca F, Merskey H: Suicidality in chronic abdominal pain: an analysis of the Hispanic Health and Nutrition Examination Survey (HHANES). Pain. 1998, 76: 137-144.PubMedGoogle Scholar
- Stenager EN, Stenager E, Jensen K: Attempted suicide, depression and physical disease: a one-year follow-up study. Psychoter Psychosom. 1994, 61: 65-73.Google Scholar
- Fishbain DA, Goldberg M, Rosomoff RS, Rosomoff H: Completed suicide in chronic pain. Clin J Pain. 1991, 7: 29-36.PubMedGoogle Scholar
- Emanuel FJ, Fairclogh DL, Daniels ER, Clarridge BR: Euthanasia and physician-assisted suicide: attitudes and experieces of oncology patients, oncologists, and the public. Lancet. 1996, 347: 1805-1810.PubMedGoogle Scholar
- Polatin PB, Kinney RK, Gatchel RJ, Lillo E, Mayer TG: Psychiatric illness and chronic low back pain. Spine. 1993, 18: 66-71.PubMedGoogle Scholar
- Heim HM, Oei TPS: Comparison of prostate cancer patients with and without pain. Pain. 1993, 53: 159-162.PubMedGoogle Scholar
- Lee J, Giles K, Drummond PD: Psychological disturbances and an exaggerated response to painin patient with whiplash injury. J Psychosom Res. 1993, 37: 105-110.PubMedGoogle Scholar
- Weissman MM, Merikangas KR: The epidemiology of anxiety and panic disorders: an update. J Clin Psychiatry. 1986, 47 (suppl): 11-17.PubMedGoogle Scholar
- Devlen J: Anxiety and depression in migraine. J R Soc Med. 1994, 87: 338-341.PubMed CentralPubMedGoogle Scholar
- Fishbain DA, Goldberg M, Meager BR, Steele R, Rosomoff H: Male and female chronic pain patients characterized by DSM-III diagnostic criteria. Pain. 1986, 26: 181-187.PubMedGoogle Scholar
- Breslau N, Davis GC: Migraine, physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Psychiatr Res. 1993, 27: 211-221.PubMedGoogle Scholar
- Kuch K, Cox BJ, Woszczyna CB, Swinson RP, Shulman I: Chronic pain in panic disorder. J Behav Ther Exp Psychiatry. 1991, 22: 255-259.PubMedGoogle Scholar
- Smedstad LM, Vaglum P, Kvien TK, Moum T: The relatioship between self-reported pain and sociodemographic variables, anxiety, and depressive symptoms in rheumatoid arthritis. J Rheumatol. 1995, 22: 514-520.PubMedGoogle Scholar
- Ready LB, Sarkis E, Turner JA: Self-reported vs actual use of medications in chronic pain patients. Pain. 1982, 12: 285-294.PubMedGoogle Scholar
- Long DM, Filtzer DL, BenDebba M, Hendler NH: Clinical features of the failed back-syndrome. J Neurosurg. 1988, 69: 61-71.PubMedGoogle Scholar
- Maruta T, Swanson DW, Finlayson RE: Drug abuse and dependency in aptients with chronic pain. Mayo Clin Proc. 1979, 54: 241-244.PubMedGoogle Scholar
- Fordice W, Fowler R, Lehmann J, Delateur BJ, Sand PL, Trieschmann RB: Operant conditioning in the treatment of chronic pain. Arch Phys Med Rehabil. 1973, 54: 399-408.Google Scholar
- Kouyanou K, Pither CE, Wessely S: Medication misuse, abuse and dependence in chronic pain patients. J Psychosom Res. 1997, 43: 497-504.PubMedGoogle Scholar
- Fishbain DA, Rosomoff HL, Rosomoff RS: Drug abuse, dependence: addiction in chronic pain patients. Clin J Pain. 1992, 8: 77-85.PubMedGoogle Scholar
- Savage SR: Addiction in the treatment of pain: significance, recognition and management. J Pain Symptom Manage. 1993, 8: 265-278.PubMedGoogle Scholar
- Compton MA: Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and abuse status. J Pain Symptom Manage. 1994, 9: 462-473.PubMedGoogle Scholar
- Stewart SH, Finn PR, Pihl RO: A dose-response study of the effects of alcohol on the perceptions of pain and discomfort due to electric shock in men at high familial-gentic risk for alcoholism. Psychopharmacology. 1995, 119: 261-267.PubMedGoogle Scholar
- Keefe FJ, Caldwell DS: Cognitive behavioural control of arthittis pain. Med Clin North Am. 1997, 81: 277-290.PubMedGoogle Scholar
- Morley S, Eccleston C, Williams A: Systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy and behavior therapy for chronic pain in adults, excluding headache. Pain. 1999, 80: 1-13.PubMedGoogle Scholar
- Eccleston C, Morley S, Williams AC, Yorke L, Mastroyannopoulou K: Systematic review of randomized controlled trials of psychological therapy for chronic pain in children and adolescents with a subset meta-analysis of pain relief. Pain. 2002, 99: 157-165.PubMedGoogle Scholar
- Bonica JJ: The management of pain. 1990, Philadelphia PA: Lee & FibigerGoogle Scholar
- Chabal C, Jacobson L, Chaney EF, et al: Narcotics for chronic pain: yes or no? A useless dichotomy. American Pain Society Journal. 1992, 1: 276-281.Google Scholar
- Porter J, Jick H: Addiction rate in patients treated with narcotics. N Engl J Med. 1980, 302: 123-PubMedGoogle Scholar
- Turk DC, Brody MC, Okifuji EA: Physicians' attitudes and practices regarding the long-term prescribing of opioids for non-cancer pain. Pain. 1994, 59: 201-208.PubMedGoogle Scholar
- Portenoy RK, Foley KM: Constipation in the cancer patient. Med Clin North Am. 1987, 71: 303-312.PubMedGoogle Scholar
- Hendler N, Cimini C, Ma T, Long D: A comparison of cognitive impairment due to benzodiazepines and narcotics. Am J Psychiatry. 1980, 137: 828-830.PubMedGoogle Scholar
- Lomardo WK, Lombardo B, Goldstein A: Cognitive functioning under moderate and low dosage methadone maintenance. International Journal of the Addictions. 1976, 11: 389-401.Google Scholar
- McNairy SI, Maruta T, Ivnik RJ, Swanson DW, Ilstrup DM: Prescription medication dependence and neuropsychological function. Pain. 1984, 18: 169-177.PubMedGoogle Scholar
- Zielger DK: Opiate and opioid use in patients with refractory headache. Cephalgia. 1994, 14: 5-10.Google Scholar
- Paoli F, Darcourt G, Corsa P: Note preliminaire su l'action de l'imipramine dans les etats douloureux. Revue de Neurologie. 1960, 2: 503-504.Google Scholar
- King RB: Neuropharmacology of depression, anxiety and pain. Clin Neurosurg. 1981, 28: 116-136.PubMedGoogle Scholar
- Mico JA, Gibert-Rahola J, Casas J, Rojas O, Serrano MI, Serrano JS: Implication of beta 1- and beta 2-adrenergic receptors in the antinociceptive effect of tricyclic antidepressants. Eur Neuropsychopharmacol. 1997, 7: 139-145.PubMedGoogle Scholar
- Bryson HM, Wilde MI: Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states. Drug Aging. 1996, 8: 459-476.Google Scholar
- Magni G: The use of antidepressants in the treatment of chronic pain a review of the current evidence. Drug. 1991, 42: 730-748.Google Scholar
- Gruber AJ, Hudson JI, Pope HG: The management of treatment-resistant depressionin disorders on the interface of psychiatry and medicine. Fibromyalgia, Chronic fatigue syndrome, migraine, irritable bowel syndrome, atypical facial pain, and premenstrual dysphoric disorder. Psychiatr Clin North Am. 1996, 19: 147-151.Google Scholar
- MacFarlane BV, Wright A, O'Callaghan J, Benson HA: Chronic neuropathic pain and its control by drugs. Pharmacol Ther. 1997, 75: 1-19.PubMedGoogle Scholar
- Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, Smoller B, Dubner R: Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987, 37: 589-596.PubMedGoogle Scholar
- McQuay H, Carrol D, Jadad AR, et al: Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995, 311: 1047-1052.PubMed CentralPubMedGoogle Scholar
- Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindstrom T, Thorell LH: A comparison of amitriptyline and maprolitine in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997, 13: 313-323.PubMedGoogle Scholar
- Wesselmann U, Reich SG: The dynias. Semin Neurol. 1996, 16: 63-74.PubMedGoogle Scholar
- Atkinson JH, Slater MA, Williams RA, Zisook S, Patterson TL, Grant I, Wahlgren DR, Abramson I, Garfin SR: A placebo-controlled randomized clinical trial of notriptyline for chronic low back pain. Pain. 1998, 76: 287-296.PubMedGoogle Scholar
- Kishore-Kumar R, Max MB, Schafer SC, Schafer SC, Gaughan AM, Smoller B, Gracely RH, Dubner R: Desipramine relieves post-herpetic neuralgia. Clin Pharmacol Ther. 1990, 47: 305-312.PubMedGoogle Scholar
- Roose SP, Glassman AH, Siris S: Comparison of imipramine and nortriptyline-induced orthostatic hypotension: a meaningful difference. J Clin Psychopharmacol. 1981, 1: 316-319.PubMedGoogle Scholar
- Watson CP, Evans RJ, Watt VR, Birkett N: Postherpetic neuralgia: 208 causes. Pain. 1988, 35: 289-298.PubMedGoogle Scholar
- Adelman JU, Von Seggern R: Cost considerations in headache treatment, Part 1: prophylactic migraine treatment. Headache. 1995, 35: 479-487.PubMedGoogle Scholar
- Gatch MB, Negus SS, Mello NK: Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys. Psychopharmacology (Berl). 1998, 135: 99-106.Google Scholar
- Paul D, Hornby PJ: Potentiation of intrathecal DAMGO antinociceptioon, but not gastrointestinal transit inhibition, by 5-Hydroxytryptamine and norepinephrine uptake blockade. Life Sci. 1995, 56: PL83-PL87.PubMedGoogle Scholar
- Schreiber S, Backer MM, Yanai J, Pick CG: The antinociceptive effect of fluvoxamine. Eur Neuropsychopharmacol. 1996, 6: 281-284.PubMedGoogle Scholar
- Belcheva S, Petkov VD, Konstantinova E, Petkov VV, Boyanova E: Effects on nociception of the Ca2+ and 5-HT receptor agonists dotarizine and other 5-HT receptor agonists and antagonists. Acta Physiol Pharmacol Bulg. 1995, 21: 93-98.PubMedGoogle Scholar
- Tokunaga A, Saika M, Senba E, Glatzeder K, Stratz T, Schwarz M, de Jonge S, Kruger M, Engel RR, Farber L, Pongratz DE, Ackenheil M: 5-HT2a receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain. 1998, 76: 349-355.PubMedGoogle Scholar
- Bondy B, Spaeth M, Offenbaecher M: The T102C polymorphism of the 5-HT2a-receptor gene in fibromyalgia. Neurobiology of Disease. 1999, 6: 433-439.PubMedGoogle Scholar
- Max M, Lynch S, Muir J, Shoaf SE, Smoller B, Dubner R: Effects of desipramine, amitriptyline and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992, 326: 1250-1256.PubMedGoogle Scholar
- Bank J: A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache. 1994, 34: 476-478.PubMedGoogle Scholar
- Foster CA, Bafaloukos J: Paroxetine in the treatment of chronic daily headache. Headache. 1994, 34: 587-589.PubMedGoogle Scholar
- Saper JR, Silberstein SD, Lake AE, Winters ME: Double-blind trial of fluvoxamine: chronic daily headache and migraine. Headache. 1994, 34: 497-502.PubMedGoogle Scholar
- Goodkin K, Gullion C, Agras WS: A randomized, double blind, placebo controlled trial of trazodone hydrocloride in chronic lowback pain syndrome. J Clin Psychopharmacol. 1990, 10: 269-278.PubMedGoogle Scholar
- Marek GJ, McDougle CJ, Price LH, Seiden LS: A comparison of trazodone and fluoxetine: implications for a serotonergic mechanism of antidepressant action. Psychopharmacology (Berl). 1992, 109: 2-11.Google Scholar
- Lang E, Hord Ah, Denson D: Venlafaxine hydrocloride (Effexor) relievs thermal hyperalgesia in rats with an experimental mononeuropathy. Pain. 1996, 68: 151-155.PubMedGoogle Scholar
- Westanmo AD, Gayken J, Haight R: Duloxetine: a balanced and selective norepinephrine- and serotonin-reuptake inhibitor. Am J Health-Syst Pharm. 2005, 6: 2481-90.Google Scholar
- Bergouignan M: Cures heureuses de nevralgies faciaales essentielles par le diphenyl-hydantoinate de soude. Rev Laryngol Otol Rhinol (Bord). 1942, 63: 34-41.Google Scholar
- Tanelian DL, Victory RA: Sodium channel-blocking agents: their use in neuropathic pain conditions. PainForum. 1995, 75-80.Google Scholar
- Lorenzo RJ: Mechanism of action of phenytoin, in Antiepileptic Drugs. Edited by: Levy RH, Dreifuss FE, Mattson RH. 1989, New York, Raven, 143-158. 3Google Scholar
- Pinelli A, Trivulzio S, Tomasoni L: Effects of carbamazepine treatment on pain threshold values and brain serotonin levels in rats. Pharmacology. 1997, 54 (3): 113-117.PubMedGoogle Scholar
- Moosa RS, McFayden ML, Miller R, Rubin J: Carbamazepine and its metabolites in neuralgias: concentration effects relations. Eur J Clin Pharmacol. 1993, 45: 297-301.PubMedGoogle Scholar
- Jensen R, Brink T, Olesen J: Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology. 1994, 44: 647-651.PubMedGoogle Scholar
- Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S, Rapoport AM, Silber CJ, Deaton RL: Migraine prophylaxis with divalproex. Arch Neurol. 1995, 52: 281-286.PubMedGoogle Scholar
- Houtchens MK, Richter JR, Sami A, Rose JW: Open label gabapentin treatment for pain in multiple sclerosis. Mult Scler. 1997, 3: 250-253.PubMedGoogle Scholar
- Wetzel CH, Connelly JF: Use of gabapentin in pain management. Ann Pharmacother. 1997, 31: 1082-1083.PubMedGoogle Scholar
- Field MJ, Holloman EF, McCleary S, Hughes J, Singh L: Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of post-operative pain. J Pharmacol Exp Ther. 1997, 282: 1242-1246.PubMedGoogle Scholar
- Canavero S, Bonicalzi V: Lamotrigine control of central pain. Pain. 1996, 68: 179-181.PubMedGoogle Scholar
- Cheung H, Kamp D, Harris E: An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res. 1992, 13: 107-112.PubMedGoogle Scholar
- Harbinson J, Dennehy F, Keating D: Lamotrigine for pain with hyperalgesia. Ir Med J. 1997, 90: 56-Google Scholar
- Leach Mj, Lees G, Riddall DR: Lamotrigine: Mechanism of action, in Proceeding of the 7th World Congress on Pain, Progress in Pain Research and Treatment. Edited by: Gebhart GF, Hammond DL, Jensen TS. 1995, Seattle, WA, IASP Press, 2: 861-869.Google Scholar
- Lees G, Leach MJ: Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex. Brain Res. 1993, 612: 190-199.PubMedGoogle Scholar
- Hollister LE, Conley FK, Britt R, Shur L: Long-term use of diazepam. JAMA. 1981, 246: 1568-1570.PubMedGoogle Scholar
- King SA, Strain JJ: Benzodiazepine use by chronic pain patients. Clin J Pain. 1990, 6: 143-147.PubMedGoogle Scholar
- Dellemijn PL, Fields HL: Do benzodiazepine have a role in chronic pain management?. Pain. 1994, 57: 137-152.PubMedGoogle Scholar
- Ganapathy S, Herrick IA, Gelb AW, Kirkby J: Propofol patient-controlled sedation during hip or knee arthroplasty in elderly patients. Can J Anaesth. 1997, 44: 385-389.PubMedGoogle Scholar
- Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH: Amitriptyline but not lorazepam, relieves postherpetic neuralgia. Neurology. 1988, 38: 1427-1432.PubMedGoogle Scholar
- Platten Hp, Schweitzer E, Dilger K, Mikus G, Klotz U: Pharmacokinetics and the pharmacodynamicaction of midazolam in young and elderly patients undergoing tooth extraction. Clin Pharmacol Ther. 1998, 63: 552-560.PubMedGoogle Scholar
- Yosselson -Superstine S, Lipman AG, Sanders SH: Adjunctive antianxiety agents in the management of chronic pain. Isr J Med Sci. 1985, 21: 113-117.PubMedGoogle Scholar
- Gear RW, Miaskovski C, Heller PH, Paul SM, Gordon NC, Levine JD: Benzodiazepine mediated antagonism of opioid analgesia. Pain. 1997, 71: 25-29.PubMedGoogle Scholar
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