Clinical Pain States Research Articles

Future of Cannabis and Cannabinoids in Therapeutics

SUMMARY This study reviews human clinical experience to date with several synthetic cannabinoids, including nabilone, levonantradol, ajulemic acid (CT3), dexanabinol (HU-211), HU-308, and SR141716 (Rimonabant®). Additionally, the concept of “clinical endogenous cannabinoid deficiency” is explored as a possible factor in migraine, idiopathic bowel disease, fibromyalgia and other clinical pain states. The concept of analgesic synergy of cannabinoids and opioids is addressed. A cannabinoid-mediated improvement in night vision at the retinal level is discussed, as well as its potential application to treatment of retinitis pigmentosa and other conditions. Additionally noted is the role of cannabinoid treatment in neuroprotection and its application to closed head injury, cerebrovascular accidents, and CNS degenerative diseases including Alzheimer, Huntington, Parkinson diseases and ALS. Excellent clinical results employing cannabis based medicine extracts (CBME) in spasticity and spasms of MS suggests extensi...

Dietary Constituents as Novel Therapies for Pain

The use of complementary and alternative medicine has dramatically increased in the United States. The effects of select dietary constituents in animal models and clinical pain states are reviewed. Specifically, the antinociceptive and analgesic properties of soybeans, sucrose, and tart cherries are discussed. The potential actions of dietary constituents as antiinflammatory and antioxidant agents are presented.

Experimental muscle pain provokes long-lasting alterations of thermal sensitivity in the referred pain area

This study explores thermal sensitivity and thermal nociception for signs of central sensitization in the area of referred muscle pain. Two groups of 24 healthy subjects (ss) each, and with mean ages of, respectively, 27 and 55 years, were first trained in quantitative sensory testing and pain rating. Then, in a second session, referred pain was evoked by injection of 6% hypertonic saline into the infraspinatus muscle. Cold and warm thresholds, synthetic heat threshold (SHT – evoked by an alternating pattern of adjacent cold and warmth), and thermal pain thresholds were measured within the referred pain area at a rate of 1/20 min for 60–120 min. All ss of both groups experienced referred pain mostly in the upper arm and of medium intensity. Pain lasted for approximately 12 min with a shorter duration in the older group ( p<0.02). The cold threshold increased significantly ( p<0.001), and the warm threshold slightly, after the injection and remained high for the whole observation period (i.e. lower and higher temperatures were necessary to elicit cold and warmth, respectively). Threshold recovery was more delayed in the older age group. Of those 28 ss in whom cold pain threshold could be followed during the whole observation period, 18 ss showed an immediate threshold decrease of average 6 °C which outlasted the observation period. Four ss responded with a threshold increase. Heat pain thresholds were not affected in the referred pain area. Average synthetic heat threshold did not change; there were, however, distinct and lasting individual threshold shifts in either direction. Ss with lowered cold pain thresholds or evident threshold shifts for synthetic heat had also higher pain ratings. The results demonstrate that experimental muscle pain can induce long-lasting changes in thermal sensitivity and nociception. The unexpected cold threshold increase may tentatively be explained as an expression of long-term depression. The decrease of cold pain threshold or SHT in subgroups of ss may indicate central sensitization. However, the observed changes in this experiment do not provide an unambiguous indicator for central sensitization which seems to be rather individual and might depend on pain intensity and proneness to express central mechanisms of sensitization. Therefore in clinical pain states the individual pattern of sensory abnormalities has to be analysed and interpreted in addition to the pain parameters to assess central involvement.

Treatment options for refractory pain: the role of intrathecal therapy.

Intraspinal drug delivery represents an important treatment option for the management of chronic pain. Selection of candidates for this type of therapy requires careful evaluation of the patient, possibly including psychological screening. Although determining the efficacy of long-term intraspinal drug therapy has been challenging, several classes of agents have been identified to provide benefits in patients with a variety of pain types. Such agents include opioids, alpha(2)-agonists, sodium channel antagonists, and gamma-aminobutyric acid agonists. In addition, combinations of agents with distinct mechanisms of action may be therapeutically advantageous because many clinical pain states result from more than one mechanism.

Persistent secondary hyperalgesia after gastrocnemius incision in the rat

Secondary hyperalgesia, an exaggerated response to stimuli applied to undamaged tissue surrounding an injury, is a common consequence of tissue injury and inflammation. It is well established that the etiology of secondary hyperalgesia is sensitization of central neurons but the exact mechanism and its role in certain clinical pain states is unclear. In the present experiments, we studied responses to punctate and non-punctate mechanical stimuli and to heat applied to the plantar aspect of the hindpaw remote to an incision in the gastrocnemius region of the rat hindlimb. Median withdrawal thresholds to von Frey filaments were reduced 2h after incision of skin, fascia and muscle (gastrocnemius incision, n = 9) and remained reduced through postoperative day 6 (p < 0.05 vs sham). Only a transient reduction in withdrawal threshold occurred after incision of skin and fascia (skin incision, n = 10). No enhanced responsiveness to blunt mechanical stimulation or reduction in withdrawal latency to heat was present after gastrocnemius incision (p > 0.05vs sham, n = 9 each group). Reduced withdrawal thresholds were blocked by i.t. administration of morphine and by local anesthetic injection at the test site 2h and 2 days after gastrocnemius incision. These pharmacological data provide evidence that reduced withdrawal thresholds after gastrocnemius incision are nociceptive behaviors indicating persistent secondary hyperalgesia. Because the behaviors have a similar time course to secondary hyperalgesia in postoperative patients, the model will be useful to evaluate the mechanisms for secondary mechanical hyperalgesia after incision, its pharmacological characteristics and its potential role in persistent postoperative pain. Copyright 2002 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Science Ltd. All rights reserved.

Genetic and hormonal basis of pain states

Among the many sources of variability in human pain and analgesic responses are influences intrinsic to the organism—genetic and hormonal factors that contribute to individual differences. This chapter serves as a review of the clinical and experimental evidence that highlights the importance of these factors in effectively understanding clinical pain states and variability in pain and analgesic responses. Epidemiological and linkage studies have been carried out in humans, and observational studies of variability in pain and analgesic responses across genders and within the menstrual cycle provide a much needed human perspective. However, the experimental approach, with its inherent explanatory power, contributes much of the knowledge in this area. Much of the basic experimental work in this area is in its early stages, but it suggests the potential for using these factors to tailor pain treatment to the individual.

Imaging the pain of low back pain: functional magnetic resonance imaging in combination with monitoring subjective pain perception allows the study of clinical pain states

Most brain imaging studies of pain are done using a two-state subtraction design (state-related design). More recently event-related functional magnetic reasonance imaging (fMRI) has also been used for studying pain. Both designs severely limit the application of the technology to clinical pain states. Recently we demonstrated that monitoring time fluctuations of perceived pain could be used with fMRI to identify brain regions involved in conscious, subjective perception of pain. Here we extend the methodology to demonstrate that the same approach can be used to study clinical pain states. Subjects are equipped with a finger-spanning device to continuously rate and log their perceived pain during fMRI data collection. These ratings are convolved with a canonical hemodynamic response function to generate predictor waveforms with which related brain activity can be identified. Chronic low back pain patients and a normal volunteer were used. In one series of fMRI scans the patient simply lies in the scanner and indicates spontaneous fluctuations of the subjective pain. In other fMRI scans, a straight-leg raising procedure is performed to exacerbate the back pain. In the normal volunteer, fMRI scans were done during painful and non-painful straight-leg raisings. The results indicate the feasibility of differentiating between different pain states. We argue that the approach can be generalized to identify brain circuitry underlying diverse clinical pain conditions.

Effects of baseline skin temperature on pain ratings to suprathreshold temperature-controlled stimuli

Variations in baseline skin temperature can be encountered in experimental and clinical pain states. Such variations have been shown to greatly alter the response to radiant heat stimuli when the temperature of the stimulus is not controlled. We carried out a psychophysical investigation to examine the influence of baseline skin temperature on pain ratings to temperature-controlled heat stimuli. A CO 2 laser thermal stimulator was used to deliver heat stimuli under radiometer feedback temperature control to the volar forearm. Each stimulus consisted of a 30 s controlled baseline interval (at 34 or 38°C) followed by a stepped increase in temperature (to 46 or 47°C for 1, 2 or 4 s). A run comprised one presentation of each of these12 different stimuli to different locations. Each experiment contained three runs. In runs 2 and 3, the stimulus intensity and duration at a given location were not changed, but the baseline temperature was alternated between 34°C and 38°C. The intensity of pain was rated using the technique of magnitude estimation. Mean normalized pain ratings for suprathreshold stimuli applied from the higher base temperature (1.03±0.03) were slightly greater than from the lower base temperature (0.96±0.03). In contrast, pain ratings to the 47°C stimuli (1.11±0.03) were substantially greater than to the 46°C stimuli (0.88±0.03). Thus a 4°C change in baseline temperature has a smaller affect (about 8%) on pain ratings than a 1°C change in stimulus temperature (about 27%). This suggests that variations in baseline skin temperature encountered in experimental and clinical pain states have only a minor impact on pain sensitivity to suprathreshold temperature-controlled stimuli.

NK 1 (substance P) receptor antagonists – why are they not analgesic in humans?

Tachykinin NK 1 receptor antagonists have failed to exhibit efficacy in clinical trials of a variety of clinical pain states. By contrast, in preclinical studies in animals NK 1 receptor antagonists have been shown to attenuate nociceptive responses sensitized by inflammation or nerve damage, although they exhibit little effect on baseline nociception. Other agents with this profile of activity in animal tests, typically nonsteroidal anti-inflammatory drugs (NSAIDs), are analgesic in humans. Thus, NK 1 receptor antagonists appear able to block behavioural responses to noxious and other stressful sensory stimuli at a level detectable in animal tests but fail to provide the level of sensory blockade required to produce clinical analgesia in humans.

Pain following spinal cord injury: pathophysiology and central mechanisms

This chapter reviews the results of experimental and clinical studies that provide insights into possible mechanism(s) underlying selected pain states following spinal injury. Emphasis is placed on studies related to central dysesthetic pain, perhaps the most disabling of all sensory complications associated with spinal cord injury (SCI). The epidemiological and clinical characteristics of different SCI pain syndromes are reviewed. The most obvious pathological characteristics associated with traumatic or ischemic injury to the spinal cord include but are by no means limited to the dramatic loss of neurons, damage to surrounding white matter, astrocytic scarring, syrinx formation, and breakdown of the spinal blood brain barrier. Common central injury cascade was proposed for the initiation of pain-related behaviors following central or peripheral injury. The different components of this central cascade are shown that include anatomical, neurochemical, excitotoxic, and inflammatory events that collectively interact to influence the functional state of spinal sensory neurons leading to the onset of different clinical pain states. Continued research directed towards specific components of the spinal injury cascade should provide a better understanding of spinal and supraspinal mechanisms responsible for this condition and the future development of novel therapeutic strategies.

International Association for the Study of Pain 9th World Congress on Pain.

International Association for the Study of Pain 9th World Congress on Pain.

Functional magnetic resonance imaging of pain consciousness: Cortical networks of pain critically depend on what is implied by “pain”

Brain imaging studies, using primarily functional magnetic resonance imaging (fMRI), are reviewed. These studies are aimed at developing imaging approaches that can be used in the clinical setting to investigate clinically relevant pain states. To this end, our recent studies indicate that by taking advantage of the temporal variations in pain perception, we are able to identify cortical regions that may be uniquely involved in pain consciousness. This procedure in turn becomes a general approach with which clinical pain states can be studied. Preliminary results are shown in patients suffering from chronic reflex sympathetic dystrophy (RSD) and chronic back pain. The review emphasizes that different experimental pain states, and chronic and acute clinical pain states, seem to involve dramatically different networks, the details of which remain to be worked out. It is concluded that these procedures need to be applied in the larger clinical setting in which multicentered studies may be conducted to begin building the brain pain network atlas.

Systemic gabapentin and S(+)-3-isobutyl-γ-aminobutyric acid block secondary hyperalgesia

Gabapentin (GBP) and S(+)-3-isobutyl-γ-aminobutyric acid (IBG) are anticonvulsant agents which are effective against many clinical and experimental neuropathic pain states. We examined the efficacy of these agents in a new rat model of secondary mechanical hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an injury was induced by applying one heel to a hot surface (52.5°C) for 45 s. GBP, IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h following the injury. MWT outside the injury area decreased post-injury (secondary hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to onset of the anti-allodynic effect of GBP was 30–60 min. The minimum effective GBP dose was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose; 100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP in this model at doses which do not cause sedation. These observations support the suggested use of these or related γ-amino acid analogues as an effective treatment for post-operative pain.

Pain

Pain: Nociceptive and Neuropathic Mechanisms with Clinical Correlates. Vol 15, No 2 of Anesthesiology Clinics of North America, M. S. Wallace, J. S. Dunn, T. L. Yaksh, eds. Philadelphia: WB Saunders, 1997, ISSN 0889-8537, 242 pp, $106.00 annual subscription for four issues. The stated goal of this quarterly monograph is twofold: first, to present to the practicing anesthesiologist the basic pharmacology and physiology of acute and chronic pain processing, and second, to discuss a selection of clinical pain states in which these principles can be applied to produce clinical benefits. At the outset, the editors state their approach to dividing preclinical and clinical information each into two sections, which reflects their view that most clinical pain states should be thought of as a composite of two different mechanisms. These mechanisms are tissue injury, such as is observed postoperatively, and nerve injury, such as is observed with diabetes or herpes zoster. The editors proceed to present abundant examples that most clinical pain states reflect contributions from both mechanisms and lie along a spectrum in which one or the other mechanism predominates. Thirteen chapters have been contributed by well known authors in the field. The book begins with a brief but interesting chapter on nociception, followed by chapters on the basic pharmacology and physiology of acute pain processing and on clinically useful drugs for perioperative analgesia. The remainder of the first half of the book provides clinical examples in which acute nociception predominates: burns, arthritis, musculoskeletal injury, sickle cell disease, and pancreatitis. The contribution of neuropathic pain to chronic postburn pain is acknowledged. Yaksh and Chaplan's chapter on neuropathic pain is a concise, timely summary of much recent work in this rapidly progressing area. Those who read it will have a better grasp of the complexities of the basic mechanisms of allodynia and the general organization of postnerve injury processes. The remainder of the second half of the volume presents thorough discussions of conditions in which neuropathic pain figures prominently: pain after mastectomy or thoracotomy, acute zoster and postherpetic neuralgia, "reflex sympathetic dystrophy" and causalgia, diabetic neuropathy, and spinal cord injury. Of the latter group, the discussions on zoster and causalgia are comprehensive yet fresh looks at topics about which much has been written. The final two chapters, which should be of interest to all pain clinics, deal with diabetic neuropathy and its sequelae and post-spinal cord injury pain states. Although all chapters and references are current, one wonders why recent advances in spinal drug delivery for spinal injury pain were not mentioned in that chapter (as they are in the discussion on reflex sympathetic dystrophy and causalgia). In summary, this issue of Anesthesiology Clinics in North America is a timely work that carefully balances a discussion of the basic physiologic mechanisms of pain and the application of this knowledge to treatment of selected pain states. The editors should be commended for their efforts in condensing the vast amount of research data and clinical experience that has accumulated in this young field. William Guptill, MD Daniel Carr, MD Department of Anesthesia; New England Medical Center; Boston, MA 02111

Multiple roles of ATP and adenosine in somatosensory processing: Therapeutic implications

A number of lines of evidence support roles for adenosine and adenosine 5′-triphosphate (ATP) in the transmission and modulation of somatosensory information in the dorsal horn of the spinal cord. Adenosine and ATP have also been demonstrated to have nociceptive (pain-related) and antinociceptive actions in the periphery. Thus, adenosine and ATP have multiple functions in somatosensory processing, which are dependent upon the site and on the relative activation of P1 and P2 purinoceptor subtypes on neurons and non-neuronal cells. The multiple roles provide a rich number of potential therapeutic targets for producing analgesia in a number of clinical pain states. However, because of the multiple and potentially contrasting pro- and anti-nociceptive roles of adenosine and ATP, pharmacological targeting of specific sites and purinoceptor subtypes will be necessary to achieve maximum effectiveness while minimizing side effects. Drug Dev. Res. 39:279–288, 1996. © 1997 Wiley-Liss, Inc.

Visceral Antinociceptive Effects of Spinal Clonidine Combined with Morphine, [D-Pen sup 2, D-Pen sup 5] Enkephalin, or U50,488H

Visceral pain is an important component of many clinical pain states. The perispinal administration of drug combinations rather than a single agent may reduce side effects while maximizing analgesic effectiveness. The purpose of this study was to examine the nature of interactions between an alpha 2-adrenergic agonist (clonidine) and a mu-opioid agonist (morphine), a delta-opioid agonist ([D-Pen2, D-Pen5] enkephalin [DPDPE]), or a kappa-opioid agonist (U50,488H). Colorectal distension was used to elicit a nociceptive visceromotor response (contraction of abdominal musculature) in rats. The ability of intrathecally administered clonidine alone or in combination with morphine, DPDPE, or U50,488H to alter thresholds for the production of the visceromotor response was examined. Clonidine produced dose-dependent reduction in threshold. U50,488H, at the doses tested, showed no synergistic interaction with clonidine. Spinal combinations of alpha 2-adrenergic and mu- or delta- but not kappa-opioid agonists may be beneficial in the control of visceral pain.

Contrasting actions of intrathecal U50,488H, morphine, or [D-Pen2, D-Pen5] enkephalin or intravenous U50,488H on the visceromotor response to colorectal distension in the rat.

Visceral sensations are an important component of many clinical pain states. It is apparent that intrathecal pain relief may be more effective if appropriate combinations of drugs rather than a single agent can be used. The purpose of this study was to examine the relative contribution of opioid receptor subtypes to visceral antinociception using colorectal distension as a visceral pain model. The minimum colorectal distending pressure necessary to evoke a visceromotor response (contraction of abdominal musculature) was determined before and after the administration of opioid agonists for the mu (morphine), delta ([D-Pen2, D-Pen5] enkephalin [DPDPE]), and kappa (U50,488H) opioid receptors. In addition to the three drugs administered intrathecally, U50, 488H was also administered intravenously. Morphine and DPDPE produced a reversible increase in threshold for activation of the visceromotor response (50% maximum possible effect [MPE] at intrathecal doses of 2.2 and 16.4 micrograms, respectively). The maximum intrathecal dose of U50,488H (100 micrograms) produced only a 20% MPE. Intravenous U50,488H produced a 50% MPE at a dose of 2.6 mg/kg. The results suggest that spinal mu- and delta- but not kappa-opioid receptors have a significant role in the modulation of visceral nociception induced by colorectal distension. In addition, the results indicate that activation of nonspinal kappa receptors may mediate visceral antinociception.

Beneficial effects of ketamine in a chronic pain state with allodynia, possibly due to central sensitization

Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous system. Clinical pain states with allodynia in connection with longstanding superficial wounds have, however, not been reported in the literature. In this case a chronic pain state developed in a previously healthy 17-year-old girl in and around a persistently suppurating appendectomy wound. There was no spontaneous pain but pronounced allodynia in the wound and in the surrounding skin. Quantitative thermal tests showed abnormal thresholds for several sensory modalities confirming abnormal processing of sensory input from the involved area. The pattern of sensory abnormalities evaluated with thermal testing changed transiently and the allodynia diminished during a phentolamine block. Since the pain responded poorly to opioids and ketamine has been reported to reduce allodynia, it was administered in a sub-dissociative bolus dose during wound dressing. The wound was essentially unchanged after treatment for 3 months but the allodynia and sensory aberrations had decreased significantly. We interpret these results as a de-sensitizing effect in the long term of repeated NMDA-receptor blockade by ketamine in a chronic pain state, with indications of central sensitization, partially maintained by sympathetic activity.

The spinal actions of nonsteroidal anti-inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects.

The traditional classification of nonsteroidal anti-inflammatory drugs (NSAIDs) as exclusively 'peripherally acting' agents is no longer valid. For many of these agents there is a growing body of evidence in favour of an additional central mechanism for their anti-inflammatory and analgesic effects. This view is further supported by the recent discovery that a substantial component of the hyperalgesia and allodynia that characterise postinjury hypersensitivity occurs in the CNS, notably the spinal dorsal horn. An important corollary is that inhibition of central nociceptive processing may represent an important analgesic mode of action for those NSAIDs that are effective in the management of pain after tissue injury. Historically, attempts to group this heterogeneous class of compounds into a single entity are largely derived from the observation that the majority of clinically useful NSAIDs are weak organic acids (pKa 3 to 5), bind extensively to plasma albumin (= 99%), and inhibit (to varying degrees) prostaglandin synthesis. However, the significance of these various unifying features is becoming increasingly obscure. While inhibition of prostaglandin synthesis apparently remains an important analgesic mode of action for NSAIDs both in the periphery and the CNS, other mechanisms should be considered. Some NSAIDs, in addition to their effects on prostaglandin synthesis, also affect the synthesis and activity of other neuroactive substances believed to have key roles in processing nociceptive input within the dorsal horn. It has been argued that these other actions, in conjunction with inhibition of prostaglandin synthesis, may synergistically augment the effects of NSAIDs on spinal nociceptive processing. Despite much effort, it remains a formidable task to assess the significance of these differential mechanisms upon clinical pain states. In the meantime, however, it may be possible, on the basis of in vivo studies, to evaluate the impact of putative spinal analgesic mechanisms that are unrelated to inhibition of prostaglandin synthesis. This approach has recently been extended to include the identification of pharmacokinetic and clinical correlates of these derived in vivo parameters, and in this way attempt to demonstrate clinical relevance.

Norbrook Lecture. Mechanisms of pain and of its control

I have tried to convey the notion that the pain system is a very flexible one. There is considerable excitement at present that we are beginning to understand the mechanisms whereby this flexibility results in clinical pain states; this must be a good prelude to trying to prevent or reverse them. But what is the relevance of all this to pain states in animals? There are still fundamental aspects about which we know too little. Detection of pain in animals is still difficult, and even when pain is present we often cannot tell how much it is affecting the animal, especially under conditions of chronic disease. We still do not know enough about the efficacy and kinetics of analgesic drugs in each species, a task for pharmacologists and clinicians alike. We know that sensitisation of nociceptive systems can occur after tissue trauma, as occurs during surgery, but we do not yet know whether this can be effectively prevented. Against this background of tasks yet to be undertaken, we can be optimistic that we are on the brink of understanding the triggers that alter pain sensitivity, that we shall soon know which mediators are involved, and that this will give rise to new strategies for the prevention as well as the alleviation of pain. There is indeed a period of excitement ahead. In all of this we must not lose sight of the ethical and welfare considerations of using animals for pain research.(ABSTRACT TRUNCATED AT 250 WORDS)