（英文版）慢性疼痛治疗方法

1084 www.thelancet.com/neurology Vol 12 November 2013 Review Combination pharmacotherapy for management of chronic pain: from bench to bedside Ian Gilron, Troels S Jensen, Anthony H Dickenson Chronic pain, a frequently neglected problem, is treated with diff erent classes of drugs. Current agents are limited by incomplete effi cacy and dose-limiting side-eff ects. Knowledge of pain processing implicates multiple concurrent mechanisms of nociceptive transmission and modulation. Thus, synergistic interactions of drug combinations might provide superior analgesia and fewer side-eff ects than monotherapy by targeting of multiple mechanisms. Several trials in neuropathic pain, fi bromyalgia, arthritis, and other disorders have assessed various two-drug combinations containing antidepressants, anticonvulsants, non-steroidal anti-infl ammatories, opioids, and other agents. In some trials, combined treatment showed superiority over monotherapy, but in others improved benefi t or tolerability was not seen. Escalating eff orts to develop novel analgesics that surpass the effi cacy of current treatments have not yet been successful; therefore, combination therapy remains an important benefi cial strategy. Methodological improvements in future translational research eff orts are needed to maximise the potential of combination pharmacotherapy for pain. Introduction Chronic pain is a common but often neglected aspect of neurological disease.1 In the USA alone, it aff ects about 30% of the population and is estimated to cost US$650 billion a year in health-care costs and lost productivity.2 Pharmacotherapy remains an important component of multimodal, multidisciplinary pain management. However, current drugs have limited effi cacy and dose-limiting toxic eff ects.3 Although translational research eff orts to develop more eff ective treatments have led to some novel agents, we have yet to address the clinical need fully.4 While awaiting better agents, and to address these limitations of current pharmacotherapy, combination drug regimens have been pursued by researchers and clinicians with the intention of improving outcomes.5,6 Combination pharma co therapy is used commonly for treatment of acute postoperative pain, and its use has a wide evidence base. Rational combination therapy has long been used in clinical areas such as asthma,7 oncology,8 and hypertension,9 but only more recently for pain management. Although more than half of patients with chronic pain receive two or more diff erent analgesic drugs concurrently,10 relatively little evidence supports this practice, and experts have called for more research on the safety and effi cacy of specifi c combination regimens.3,11 Through knowledge of pain processing, many con- current mechanisms of nociceptive transmission and modulation can be targeted.12 Thus, synergistic interactions between mechanistically distinct analgesic drugs might provide superior analgesia or fewer side-eff ects compared with monotherapy.13,14 In this Review, we discuss preclinical literature, clinical data, and other information addressing the rationale, practice, and future directions of combination pharmacotherapy for pain. We do not review combination treatment for headache, which is discussed elsewhere.15 Pain mechanisms and clinical classifi cation Nociceptive processing represents an important alarm system to warn of tissue damage.12,16,17 Pain is signalled by specialised high-threshold receptors in the periphery, leading to a less well-defi ned emotional experience, driving the individual to escape from the noxious stimulus.18 Acute nociceptive pain occurs only in the presence of noxious stimuli and resolves shortly after removal of the stimulus. Chronic pain, however, seems to serve no purpose. It is a state in which increased activity is present in the nociceptive signalling system because of either sustained input in peripheral sensory nerves or abnormal activity in those parts of the nervous system that modulate sensory information. This abnormal modulation can lead to either increased facilitation in central zones or insuffi cient inhibition in pain-transmitting and pain- modulating circuits.12,19,20 Chronic pain is typically divided into three major classes: infl ammatory (eg, arthritis), neuropathic (eg, postherpetic neuralgia), and idiopathic (eg, fi bro myalgia). These classifi cations are adapted mainly from preclinical evidence from which distinct and separable mechanisms have been identifi ed from neuropathic and infl ammatory models, and there are various diff erent diseases and causes; in the case of neuropathic pain, these can be categorised according to the assumed underlying pathology and the anatomical location of the disorder (table 1). Infl ammatory pain is a response to tissue injury and is accompanied by neurogenic infl ammation.12,21,22 It results from the release of sensitising infl ammatory substances (eg, prostanoids, bradykinin) that reduce the activation threshold of the nociceptors innervating the infl amed tissue, increasing the response to activation and yielding abnormal responses in the CNS to sensory inputs as a result of increased neuronal excitability. These events, although evoked within minutes, can outlast the tissue injury for hours to days. Tissue changes after infl ammation are reversible if healing occurs, and the sensitivity of the system is restored after infl ammation has resolved. In chronic infl ammatory conditions, nociceptive signalling pathways are intact and in a state of heightened sensitivity to ensure optimum healing. Signs of Lancet Neurol 2013; 12: 1084–95 Published Online September 25, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70193-5 Departments of Anaesthesiology and Perioperative Medicine and Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada (Prof I Gilron MD); Department of Neurology and Danish Pain Research Centre, Aarhus University Hospital, Aarhus, Denmark (Prof T S Jensen MD); and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK (Prof A H Dickenson) Correspondence to: Prof Ian Gilron, Anaesthesiology and Perioperative Medicine, Queen’s University, Kingston, ON, Canada K7L 2V7 gilroni@queensu.ca www.thelancet.com/neurology Vol 12 November 2013 1085 Review infl ammation—such as swelling, redness, and increased temperature—are usually present. As a result, pain in the infl amed body area partly promotes avoidance from contact or movement and, thus, protection from further damage. Neuropathic pain follows injury or disease aff ecting peripheral nerves or sensory pathways within the spinal cord or brain.23 Neuronal lesions result in sensory loss in the territory corresponding to damaged nerves or to the peripheral projections of CNS structures. Therefore, an important distinction from infl ammatory pain is that neuropathic pain can sometimes be combined paradoxically with sensory loss in the painful area.24 Idiopathic pain, or pain of unknown origin, refers to a group of disorders (eg, fi bromyalgia, chronic whiplash) in which the underlying mechanisms are poorly understood. The general absence of infl ammation, nerve injury, major psychiatric illness, or other documentable pathological features is such that these conditions represent diagnoses of exclusion. A feature of idiopathic pain is a local or generalised increase in sensitivity to noxious and non-noxious stimuli.19,20,25 Idiopathic pain has also been termed functional or dysfunctional pain. These terms should be avoided because they carry the connotation that these symptoms might represent malingering (the conscious simulation of painful symptoms), which is a very rare condition26 and clearly diff erent from idiopathic pain. These pain subcategories are somewhat artifi cial and do not respect individual variations. Patients can present with diverse pain complaints not necessarily accounted for by a purely infl ammatory or neuropathic cause, and in many cases a chronic pain condition might represent a mixture of these diff erent subcategories. For example, in osteoarthritic pain such as lower back pain, which is normally classifi ed as an infl ammatory type of pain, additional neuropathic (eg, an irritant eff ect on aff erent nerve fi bres from infl amed tissue) and even neuroplastic (eg, sustained peripheral activity causing central sensitisation) components can be present. A characteristic of most pain conditions, irrespective of cause, is a set of common signs that include elicitation of pain by low threshold input, spread of pain outside the injured territory, pain that outlasts stimulation, and an augmentation of pain with repetitive stimuli (temporal summation). These common events are attributable to sensitisation within the CNS, which is defi ned as amplifi cation of neuronal activity within the CNS that gives rise to hypersensitivity in sensory processing, including increased pain sensitivity.20 Although central sensitisation is activity-dependent and driven from the periphery, it can also become self- sustained once developed and enhanced or recruited by central mechanisms, such as loss of inhibition in central descending pathways27 or increased activity in noxious facilitating systems within the CNS.28,29 Pain diagnosis and identifi cation of underlying pathological processes require clinical examination,19 which can be facilitated by diff erent available questionnaires that, with reasonable sensitivity and specifi city, can distinguish between neuropathic and non-neuropathic pain. These questionnaires include the Leeds assessment of neuropathic symptoms and signs (LANNS) scale, painDETECT, ID-Pain, and douleur neuropathique 4 (DN4).30 However, they do not identify specifi c pathological features or causes and, for that reason, a clinical examination is mandatory. In addition to clinical assessment, a careful sensory examination should be done to elicit the hypoaesthetic and hyperaesthetic abnormalities that characterise neuropathic pain. Pharmacological treatment A major goal of pain management is to provide pain relief that is clinically meaningful, sustained, and associated with minimum and reversible adverse eff ects.11 Defi ning what is a clinically meaningful reduction in pain is challenging, and only a few studies have attempted to do so. Secondary analyses from a group of industry-sponsored chronic pain trials suggest that a 30% pain reduction is clinically meaningful.31 In some settings, a lower level of relief can be meaningful if there are few adverse eff ects. Because chronic pain is sometimes associated with mood disturbance, anxiety, and sleep interference,32 pain treatments that concurrently improve these other symptoms are preferred. However, some CNS-depressant eff ects might impair a patient’s mobility and ability to exercise, which are crucial for successful rehabilitation in several pain conditions. Table 2 lists recent consensus recommendations for pharmacological treatment of chronic non-malignant pain.11,33–35 Chronic pain is generally characterised by heightened sensitivity and increased response to noxious stimuli (hyperalgesia) and pain produced by normally non-noxious stimuli (allodynia).19 This sensory hyper excitability can often be suppressed by analgesics, including anticonvulsants, antidepressants, and Peripheral Spinal Brain Genetic Fabry neuropathy Syringomyelia Syringobulbia Metabolic Painful diabetic neuropathy B12 myelopathy .. Traumatic Nerve injury Spinal cord injury .. Vascular Vasculitic neuropathy Spinal cord stroke Stroke Neoplastic Tumour compression neuropathy Tumour compression Tumour compression Immunological Guillain-Barré syndrome Multiple sclerosis Multiple sclerosis Infectious HIV, borreliosis Infectious myelitis Encephalitis Toxic Chemotherapy neuropathy .. .. Characteristic examples are provided within every category. Table 1: Classifi cation of neuropathic pain according to site of injury and type of pathology 1086 www.thelancet.com/neurology Vol 12 November 2013 Review opioids.36 These antihyperalgesic drugs exert their eff ects respectively on Ca²+ channels, Na+ channels, monoamine uptake mechanisms, and G-protein- coupled membrane receptors expressed in neurons that are widespread throughout the nervous system in peripheral, spinal, brainstem, limbic, and cortical structures. As such, CNS depressants also potentially cause sedation, dizziness, and memory problems, whereas combinations of drugs with additive analgesic eff ects but not cumulative adverse eff ects represent a possibility to lower the dose of single agents and thereby reduce side-eff ects. Combination pharmacotherapy Effi cacy of single agents for chronic pain is limited, with less than a third of patients reporting at least moderate pain relief. So, there is a need either to develop new and more eff ective drugs or to identify favourable combinations of drugs that are already available. Several concurrent neural mechanisms of pain modulation have a role in clinical syndromes, providing a strong rationale for combination pharmacotherapy. While addressing the limitations of current treatments, intense translational research eff orts have led to an explosion of knowledge about novel pain mechanisms and pharmacological targets.12 However, as with other areas of neurotherapeutics, this work has not yet provided a solution to control pain, although some improved pain treatments have been developed.4 In clinical practice, the observation of partial benefi t with one analgesic can lead prescribers to pursue polypharmacy in an add-on fashion.37 In fact, recent reports indicate that more than half of patients with chronic pain receive two or more diff erent analgesic drugs concurrently.10 The fi ndings of some studies show that specifi c combinations provide no additional benefi t or, worse yet, increase adverse eff ects. In lumbar radiculopathy, monotherapy with either nortriptyline or morphine failed to show effi cacy, and the combination of the two drugs provided no added benefi t.38 In phantom limb pain, ketamine—but not calcitonin— showed effi cacy, but their combination was no better than ketamine alone.39 Finally, in post-herpetic neuralgia, combining the phenothiazine agent fl uphenazine with amitriptyline provided no added analgesia compared with amitriptyline alone, although sedation was increased.40 These and other examples emphasise the need for expanded research on com- bination pharmacotherapy, both from mechanistic and empirical perspectives, to identify benefi cial com- binations and to guide selection of combinations in a rational manner. Broadly speaking, addition of a second drug to an eff ective but suboptimum fi rst drug could have several eff ects. First, better pain reduction could occur by addition of a second analgesic, either through complementary actions or actions that in some other way potentiate the effi cacy of the fi rst drug. Second, an improved side-eff ect profi le might be noted either with a second drug that directly antagonises the adverse eff ects of the fi rst drug (eg, an opioid plus a CNS stimulant) or with a combination that provides maximum analgesia at such low doses that overall side- eff ects are reduced. Finally, expanded improvement of other related symptoms (eg, sleep disturbance, depression, anxiety) might be seen—eg, night-time addition of a sedating antidepressant drug to a non- steroidal anti-infl ammatory (NSAID). Another rationale for combination therapy is to target the diff erent pain mechanisms that coexist within an individual—eg, a patient with infl ammatory and neuropathic causes of low back pain could benefi t from both an anti- infl ammatory and an antineuropathic treatment. Pain modulation and mechanistic rationale for combination therapy Advanced preclinical research methods facilitate investigation of mechanisms underlying neuropathic and infl ammatory pain, thereby enabling development First-line and second-line recommendations Third-line and fourth-line recommendations Not recommended Neuropathic pain11 First-line: tricyclic antidepressants, SNRI antidepressants, anticonvulsants (gabapentin or pregabalin); second-line: tramadol, opioids Bupropion, citalopram, paroxetine, carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid, dextromethorphan, memantine, and mexiletine ·· Osteoarthritis of the hip or knee33 Paracetamol, NSAIDs, tramadol ·· Chondroitin sulfate, glucosamine, opioids, duloxetine Fibromyalgia34 Muscle relaxants, tricyclic antidepressants, SSRI and SNRI antidepressants, tramadol, anticonvulsants (gabapentin or pregabalin) ·· Opioids* Low back pain35 Paracetamol, NSAIDs, COX2 inhibitors, muscle relaxants, tramadol Opioids†, antidepressants, anticonvulsants Benzodiazepines, systemic corticosteroids We have summarised recommendations from consensus statements from the last decade. COX2=cyclo-oxygenase-2. NSAIDs=non-steroidal anti-infl ammatory drugs. SNRI=serotonin–noradrenaline reuptake inhibitor. SSRI=selective serotonin reuptake inhibitor. *Third-line recommendation by only one of three consensus statements. †Reported as potentially harmful by some consensus statements Table 2: Systemic pharmacological treatments recommended for management of chronic non-malignant pain www.thelancet.com/neurology Vol 12 November 2013 1087 Review of more eff ective treatments. The peripheral mechanisms of these two pain subtypes are very diff erent and treatments vary, yet signalling systems within the CNS seem to be common. In idiopathic pain disorders, such as fi bromyalgia, the underlying mechan isms of pain are more likely to be central, although recent evidence also points to possible peripheral mechanisms in some patients.41 Within a pain syndrome, many mechanisms are clearly in operation at peripheral and central sites (fi gure 1). The pivotal issue lies in identifi cation of the pain-modulating role of signalling molecules in the context of the whole animal and then translating this knowledge to the patient. The net balance of activity within the nervous system establishes the fi nal sensation. Thus, in-vivo models (ie, integrated systems) Potential reorganisation Idiopathic pain Altered central processing Neuropathic pain Lesion or disease-altering ion-channel function Ongoing and enhanced activity in sensory and affective areas Autonomic changes Sleep disturbances Excess excitation Failure of inhibition Central sensitisation Altered sensory coding Inflammatory pain Chemical mediators acting on nociceptors Dorsal columns Descending controls favour facilitation Spinothalamic tract Noradrenaline (–) Limbic pathways PAG RVM (–) α2R (+) 5-HT3R A7 LC A5 CC Po Am LC PB NGCN VPM/ VPL Hyp Enhanced pain messages Comorbidities: anxiety and depression Previous experience Descending facilitatory control Somatosensory cortex (via thalamic relays) Intensity and location of pain Amygdala Fear, anxiety, aversion Peripheral sensory fibres Transduction and transmission of sensory modalities Spinal cord Integration of incoming messages; amplification and modulation; neurotransmitter release and neuronal excitability Descending controls Modulation of spinal activity through excitatory and inhibitory events Opioids TCAs SNRIs Opioids TCAs SNRIs Opioids TCAs SNRIs NSAIDs NSAIDs Pregabalin Gabapentin Lidocaine Capsaicin Carbamazepine Lidocaine NMDA blockers Serotonin (+/–) Figure 1: Main pathways and mechanisms by which pain is transmitted and modulated The ascending pathways, by which sensory and aff ective components are generated, are shown on the left. Top-down modulation, by which higher ce