Stimulation-produced analgesia: acupuncture,TENS and related techniques

Stimulation-produced analgesia (SPA) is a term that describes many techniques, both non-invasive and invasive. These techniques relieve pain via both peripheral and central mechanisms. Simple antidromic conduction of non-painful stimuli (electrical or physical) and gate control of noxious impulses typically produce rapid analgesia of short duration. Longer-term effects are dependent on production of endogenous opioids at spinal cord and brain level and activation of non-opioid transmitter systems in the limbic system and at the spinal gate. There is no scientific evidence that metaphysical (without form or substance) energy pathways play any role in SPA. Methods of producing analgesia by nerve stimulation include non-invasive or minimally invasive techniques such as acupuncture, transcutaneous electrical nerve stimulation (TENS) and acupressure. Good evidence indicates that they are useful as a sole or supplementary analgesic technique for many painful conditions, both acute and chronic. Electronic stimulators may also be permanently implanted at peripheral nerves, into the epidural space or into the brain. These invasive techniques are useful for refractory pain conditions, mostly of neuropathic origin.     

Implantable technology for pain management

Neuropathic pain is a well-recognized chronic pain condition. This can have a significant impact on patients' quality of life. Neuromodulation is defined by the International Neuromodulation Society as ‘the therapeutic alteration of activity in the central or peripheral nervous system either electrically or pharmacologically’. Electrical stimulation can be performed at the motor cortex, deep brain, spinal cord, dorsal root ganglion, peripheral nerve and peripheral nerve field. Pharmacological modulation is achieved by directly infusing drugs to the central nervous system. Although neuromodulation has become increasing popular, it is still currently believed to be underused in treating neuropathic pain. This modality has provided us with a non-pharmacological approach to manage patients with neuropathic pain. Patients should have been assessed by a multidisciplinary team before undergoing neuromodulation. This review highlights the present and future management of patients with chronic intractable pain using neuromodulation.     

Implantable technology for pain management

Neuropathic pain is a well-recognized chronic pain condition. This can have a significant impact in patients' quality of life. Neuromodulation is defined by the International Neuromodulation Society as ‘the therapeutic alteration of activity in the central or peripheral nervous system either electrically or pharmacologically’. Electrical stimulation can be performed at the motor cortex, deep brain, spinal cord, dorsal root ganglion, peripheral nerve and peripheral nerve field. Pharmacological modulation is achieved by directly infusing drugs to the central nervous system. Although neuromodulation has become increasing popular, it is still currently believed to be underused in treating neuropathic pain. This modality has provided us with a non-pharmacological approach to manage patients with neuropathic pain. Patients should have been assessed by a multidisciplinary team before undergoing neuromodulation. This review highlights the present and future management of patients with chronic intractable pain using neuromodulation.     

Spinal cord anatomy,pain, and spinal cord stimulation mechanisms

The effectiveness and mechanisms of spinal cord stimulation described in literature rely on a proper understanding of spinal cord anatomy and pain theory. In this article we provide an overview of relevant spinal cord anatomy, pain mechanisms, and theories of pain perception. This includes the gate control theory that is the foundation for spinal cord stimulation as a treatment for chronic pain. Thereafter, we describe the different mechanisms of spinal cord stimulation. Specifically, there are considerations in anatomy, electrophysiology, neurochemistry, and neurophysiology of the central nervous system that play a role in how spinal cord stimulation modulates the pain “gate” system.     

Augmentative treatment of chronic deafferentation pain syndromes after peripheral nerve lesions.

Deafferentation pain syndromes developing after peripheral nerve lesions are difficult to treat. According to the follow-up (mean: 39.5 months) of 6 patients suffering from causalgic pain we will present our method of augmentative therapy in chronic neuropathic pain caused by peripheral nerve lesions, i.e., peripheral nerve stimulation (PNS), spinal cord stimulation (SCS) and chronic intrathecal opioid infusion. None of the patients showed intraoperative or follow-up complications. Evaluated by visual analogue scales all patients reported a good to excellent pain relief (75-100%). (1) Regarding the favourable long-term results of PNS, this method should be considered in cases of mononeuropathic pain syndromes. (2) Neuropathic pain syndromes which are not assignable to a singular nerve lesion, can often be managed effectively by SCS. (3) In contrast to the widespread opinion, deafferentation pain syndromes of central or peripheral origin can be treated satisfactorily by intrathecal opiate administration.     

Pain management after lower extremity amputation

Phantom pain may occur in up to 85% of patients after limb amputation. Although the pathophysiology of postamputation phantom pain is not well understood, it seems to be produced by a complex multifactorial interaction between the peripheral, sympathetic, and central nervous systems. The theoretical aspects of this are reviewed. Management of phantom limb pain may be both medical and surgical. Among the pharmacological agents proved effective against phantom pain are beta-blockers, tricyclic antidepressants, and anticonvulsants. Surgical management includes peripheral nerve stimulation, thermocontrolled coagulation of the spinal cord, spinal cord stimulation, transcutaneous nerve stimulation, and stereotactic deep brain stimulation.     

Oral Donepezil Reduces Hypersensitivity after Nerve Injury by a Spinal Muscarinic Receptor Mechanism

Background: Cholinesterase inhibitors which reach the central nervous system produce pain relief but are poorly tolerated because of gastrointestinal side effects. Here, the authors tested whether donepezil, a central nervous system penetrant cholinesterase inhibitor with a low incidence of gastrointestinal side effects, would relieve hypersensitivity in an animal model of neuropathic pain.

Methods: Male rats were anesthetized, and the L5 and L6 spinal nerves were ligated unilaterally. Hypersensitivity was measured by withdrawal threshold to von Frey filament application to the hind paw after oral donepezil, and antagonists administered centrally and peripherally. Efficacy of chronic oral donepezil to relieve hypersensitivity was tested, and activation of G proteins by M2 muscarinic receptors was determined by carbachol-stimulated [35S]guanosine triphosphate [gamma]S autoradiography in brain and spinal cord.

Results: Spinal nerve ligation resulted in hypersensitivity that was more severe ipsilateral than contralateral to surgery. Oral donepezil reduced hypersensitivity bilaterally in a dose-dependent manner for 2 h, and this effect was blocked by spinal but not supraspinal or peripheral muscarinic receptor antagonism. Oral donepezil maintained efficacy over 2 weeks of twice daily administration, and this treatment did not lead to desensitization of muscarinic receptor-coupled G proteins in brain or spinal cord.     

Oral donepezil reduces hypersensitivity after nerve injury by a spinal muscarinic receptor mechanism

BACKGROUND: Cholinesterase inhibitors which reach the central nervous system produce pain relief but are poorly tolerated because of gastrointestinal side effects. Here, the authors tested whether donepezil, a central nervous system penetrant cholinesterase inhibitor with a low incidence of gastrointestinal side effects, would relieve hypersensitivity in an animal model of neuropathic pain. METHODS: Male rats were anesthetized, and the L5 and L6 spinal nerves were ligated unilaterally. Hypersensitivity was measured by withdrawal threshold to von Frey filament application to the hind paw after oral donepezil, and antagonists administered centrally and peripherally. Efficacy of chronic oral donepezil to relieve hypersensitivity was tested, and activation of G proteins by M(2) muscarinic receptors was determined by carbachol-stimulated [(35)S]guanosine triphosphate (gamma)S autoradiography in brain and spinal cord. RESULTS: Spinal nerve ligation resulted in hypersensitivity that was more severe ipsilateral than contralateral to surgery. Oral donepezil reduced hypersensitivity bilaterally in a dose-dependent manner for 2 h, and this effect was blocked by spinal but not supraspinal or peripheral muscarinic receptor antagonism. Oral donepezil maintained efficacy over 2 weeks of twice daily administration, and this treatment did not lead to desensitization of muscarinic receptor-coupled G proteins in brain or spinal cord. CONCLUSIONS: Donepezil, a well-tolerated cholinesterase inhibitor used in the treatment of Alzheimer dementia, reduces hypersensitivity in this rat model of neuropathic pain by actions on muscarinic receptors in the spinal cord. Lack of tolerance to this effect, in contrast to rapid tolerance to direct receptor agonists, suggests that cholinesterase inhibition may be useful in the treatment of neuropathic pain.     

Electrical stimulation for the control of pain.

Electrical stimulation for the control of pain is now a well accepted therapeutic modality. Transcutaneous application of electrical stimulation is the most common technique employed and has been used to treat chronic pain, acute surgical pain, and acute pain of other origins. Percutaneous application of electricity to the nervous system through needles electrodes is useful in predicting the efficacy of implantable stimulators and has served the same function as diagnostic nerve block. Implantable stimulators have been used for stimulation of peripheral nerves, the anterior and posterior surfaces of the spinal cord, and the brain. Peripheral nerve stimulators are the most efficacious of the implantable devices. They are used specifically for pain of peripheral nerve injury origin. Their use for pain outside the distribution of the nerve stimulated is not yet proved.     

History of neuroaugmentative procedures

Neuroaugmentation, the use of chronic stimulation of the brain and spinal cord for pain management, developed during the past 30 years. It evolved, however, from concepts of pain treatment that were based on observations and clinical experience dating back an additional two decades or more. The appreciation of the role of the extralemniscal system and descending influences from the brain in modulation of pain perception led to the Melzack-Wall gate theory. The concept proposed in that theory, that pain perception could be lessened by increasing activity in neural structures not associated with pain, led to chronic stimulation of deep brain and spinal cord as a modality for the management of chronic pain. Both brain and spinal structures emerged as targets for neuroaugmentation.     

Complex regional pain syndrome--diagnostic,mechanisms, CNS involvement and therapy

Complex regional pain syndromes (CRPS, formerly reflex sympathetic dystrophy and causalgia) are neuropathic pain conditions of one extremity developing inadequately after a trauma. The initiating trauma affects primarily the extremity, but can also be a central lesion (e.g., spinal cord injury, stroke). CRPS is clinically characterized by sensory, autonomic and motor disturbances. Pathophysiologically there is evidence for functional changes within the central nervous system and for involvement of peripheral inflammatory processes. The sympathetic nervous system plays a key role in maintaining pain and autonomic dysfunction in the affected extremity. After a primary central lesion, secondary peripheral changes in the paretic extremity are suggested to be important in initiating a CRPS. Though there is no diagnostic gold standard, careful clinical evaluation and additional test procedures should lead to an adequate diagnosis. An early diagnosis and an interdisciplinary approach are important for optimal and successful treatment.     

Role of the neurosteroid allopregnanolone in the hyperalgesic behavior induced by painful nerve injury in rats

The neurosteroid allopregnanolone (AP) influences the excitability of the central nervous system by acting as a positive allosteric modulator of γ-aminobutyric acid type A (GABA_A) receptors. Here, we investigated the role of AP and its therapeutic potential in rats that showed hyperalgesic behavior after undergoing spinal nerve ligation (SNL). AP levels measured in the spinal cord and brain of rats that underwent SNL were greater than the corresponding levels in control animals. More importantly, spinal AP levels in hyperalgesic rats were lower than those in the rats that did not develop hyperalgesia following SNL; in contrast, brain AP levels were comparable among these groups. No differences in serum AP levels were observed among the groups. In addition, intrathecal exogenous administration of AP showed the antihyperalgesic effects in hyperalgesic rats after SNL. These findings suggest that changes in spinal AP biosynthesis are involved in the pathogenesis of neuropathic pain following peripheral nerve injury, and pharmacological manipulation of this phenomenon may provide a potential therapeutic target for neuropathic pain.     

Neurosurgical approaches to pain treatment

In a multidisciplinary approach to the management of chronic pain, neurosurgical methods are an indispensable part of the therapeutic armamentarium. With the exception of percutaneous interventions for trigeminal neuralgia and facet joint syndromes, most ablative pain surgery procedures (neurotomy, rhizotomy, sympathectomy, etc.) have been replaced by neuromodulatory approaches such as electrical stimulation of the central nervous system (CNS). However, cordotomy is still a valuable operation for certain forms of cancer related pains (Pancoast's syndrome, breakthrough pain) which are relatively resistant to pharmacotherapy. Another example of ablative surgery is the dorsal root entry zone (DREZ) operation, which is generally the only treatment option for pain due to root avulsion and segmental pain in spinal cord injury. Spinal cord stimulation (SCS) has proven to be most useful for the management of pain following peripheral nerve injury (including complex regional pain syndromes) and rhizopathy. For these conditions which are otherwise often therapy resistant, SCS may produce substantial and long-lasting pain relief in 60-70% of the patients. Considering that such pains are common and the fact that SCS has been shown to be cost-effective, this treatment is no doubt at present underused. Complications and side-effects are very rare. SCS has also been found to be useful for pain in peripheral vascular disorders and angina pectoris. In the latter condition the overall results are favorable in about 80% of patients with a significant reduction of the frequency and severity of angina attacks and the need for nitrates. Stimulation of the motor cortex is a novel and promising treatment of central, post-stroke pain and painful trigeminal neuropathy.     

Schmerzsyndrome mit kausaler Beteiligung des Sympathikus

The efferent sympathetic nervous system is organized into subsystems that innervate and regulate via separate peripheral sympathic pathways the different autonomic target organs. This review discusses mechanisms through which this efferent system may be causally involved in the generation of pain. Clinical pain syndromes in which this may be the case are ?complex regional pain syndromes” (CRPS) type I (previously reflex sympathetic dystrophy) and type II (recently causalgia). The ?sympathetically maintained pain” (SMP) is a symptom (and not a clinical entity) that can principally also be present in other pain syndromes. An explanatory hypothesis, which may explain the clinical phenomenology of CRPS (different types of pain, swelling, autonomic, motor and trophic changes) and the mechanisms involved, is described and discussed. This hypothesis consists of different components that either have been tested and verified experimentally or which are still hypothetical. The hypothesis consists of changes in the primary afferent (nociceptive and non-nociceptive) neurones (sensitization, ectopic impulse generation) and of the neurones in the spinal cord (preferentially in the dorsal horn) which are secondary consequences of the changes in the primary afferent neurones (?central sensitization”). These changes are not specific for SMP. The centerpiece of the hypothesis is a positive feedback circuit that consists of the primary afferent neurones, spinal cord neurones, sympathic neurones and the pathologic sympathetic-afferent coupling. This coupling can occur directly via noradrenaline (or possibly another substance) at different sites of the afferent neurone (at the lesion site, remote from the lesion site in the periphery and in the spinal ganglion). The direct coupling requires that the afferent neurone expresses adrenoceptors. Indirect coupling can occur via the vascular bed or otherwise, e.g. by changes of the neurovascular transmission. The activity in the sympathetic neurones to the affected extremity can change. This change does not consist of a generalized increase of sympathetic activity but of a change of the reflexes (e.g., thermoregulatory and nociceptive reflexes). From this follows that the pathophysiologal processes operating in CRPS may occur at four levels of integration that interact with each other: effector organ, peripheral afferent and sympathetic neurone, spinal cord, supraspinal centres. Recent experimental investigations on rats show that the sympathetic nervous system is possibly also causally involved in the generation of inflammation and inflammatory pain. The mechanisms by which this occurs are different from those operating in SMP during CRPS.     

Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence

This review discusses the control of the urethra by the central nervous system, emphasizing the importance of nervous system control and the role of serotonin and noradrenaline in storage, micturition and sphincter reflexes. The concept of pharmacological neuromodulation and the use of pharmacological therapy as first-line therapy for stress urinary incontinence (SUI) is presented. Coordination between the urinary bladder and urethra is mediated by many reflex pathways organized in the brain and spinal cord. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes depend on interneuronal circuitry in the spinal cord and are modulated by descending pathways. It would therefore seem that neurotransmission in the central nervous system and periphery may be important in SUI, and moreover that pharmacological agents affecting these neurotransmitter pathways may be used to treat SUI. The central and peripheral mechanisms of action of duloxetine affect serotonin and noradrenaline neurotransmission in ways that may ameliorate the symptoms of SUI.     

Repeated injury to the lumbar nerve roots produces enhanced mechanical allodynia and persistent spinal neuroinflammation.

STUDY DESIGN: A lumbar radiculopathy model investigated pain behavioral responses after nerve root reinjury. OBJECTIVES: To gain a further understanding of central sensitization and neuroinflammation associated with chronic lumbar radiculopathy after repeated nerve root injury. SUMMARY OF BACKGROUND DATA: The pathophysiologic mechanisms associated with chronic radicular pain remain obscure. It has been hypothesized that lumbar root injury produces neuroimmunologic and neurochemical changes, sensitizing the spinal cord and causing pain responses to manifest with greater intensity and longer duration after reinjury. However, this remains untested experimentally. METHODS: Male Holtzman rats were divided into two groups: a sham group having only nerve root exposure, and a chromic group in which the nerve root was ligated loosely with chromic gut suture. Animals underwent a second procedure at 42 days. The chromic group was further divided into a reinjury group and a chromic-sham group, in which the lumbar roots were only re-exposed. Bilateral mechanical allodynia was continuously assessed throughout the study. Qualitative assessment of spinal cord glial activation and IL-beta expression was performed. RESULTS: Mechanical allodynia was significantly greater on both the ipsilateral and contralateral sides after reinjury (P < 0.001), and the response did not return to baseline after reinjury, as it did with the initial injury. There were also persistent spinal astrocytic and microglial activation and interleukin-1beta expression. CONCLUSIONS: The bilateral responses support central modulation of radicular pain after nerve root injury. An exaggerated and more prolonged response bilaterally after reinjury suggests central sensitization after initial injury. Neuroinflammatory activation in the spinal cord further supports the hypothesis that central neuroinflammation plays an important role in chronic radicular pain.     

Transient receptor potential A1 receptor‐mediated neural cross‐talk and afferent sensitization induced by oxidative stress: Implication for the pathogenesis of interstitial cystitis/bladder pain syndrome

Although the pathogenesis of interstitial cystitis/bladder pain syndrome remains unknown, there is a significant correlation of interstitial cystitis/bladder pain syndrome with other chronic pain disorders, such as irritable bowel syndrome, endometriosis and fibromyalgia syndrome. In this review, we highlight evidence supporting neural cross‐talk in the dorsal root ganglia, spinal cord and brain levels, which might play a role in the development of chronic pain disorders through central sensitization. In addition, we focus on transient receptor potential V1 and transient receptor potential A1 as the receptor targets for chronic pain conditions, because transient receptor potential V1 and transient receptor potential A1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene‐related peptide in nociceptive sensory neurons. Furthermore, peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of transient receptor potential V1 and transient receptor potential A1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously. The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross‐talk. Because oxidative stress is considered to induce activation of transient receptor potential A1, we also discuss exogenous and endogenous oxidative stress to elucidate its role in the pathogenesis of interstitial cystitis/bladder pain syndrome and other chronic pain conditions.     

The painful consequences of peripheral injury

Peripheral damage is immediately assessed by the central nervous system by way of a gate control system so that the sensory outcome depends not only on the fact of the injury and the injury signals but also on other convergent impulses from the periphery and on descending controls from brain to spinal cord. However peripheral injury, particularly when nerves are affected, sets off a chain of slow reactions which start in the area of damage but spread centrally. There are the local inflammatory reactions which change the sensitivity of nerves or of sprouts growing from cut nerves. There are changes which move over the entire length of the damaged axon changing the dorsal root ganglia and the terminals of afferents within the spinal cord. The arrival of injury produced impulses in the spinal cord triggers changes with a latency of many minutes which persist for hours even if no further impulses arrive. These increases of excitability and expansion of receptive fields which are triggered by C fibres may be the basis of the secondary hyperalgesias and reflex changes associated with injury.     

Voiding reflex in chronic spinal cord injured cats induced by stimulating and blocking pudendal nerves

AIMS: To induce efficient voiding in chronic spinal cord injured (SCI) cats. METHODS: Voiding reflexes induced by bladder distension or by electrical stimulation and block of pudendal nerves were investigated in chronic SCI cats under alpha-chloralose anesthesia. RESULTS: The voiding efficiency in chronic SCI cats induced by bladder distension was very poor compared to that in spinal intact cats (7.3 +/- 0.9% vs. 93.6 +/- 2.0%, P < 0.05). In chronic SCI cats continuous stimulation of the pudendal nerve on one side at 20 Hz induced large amplitude bladder contractions, but failed to induce voiding. However, continuous pudendal nerve stimulation (20 Hz) combined with high-frequency (10 kHz) distal blockade of the ipsilateral pudendal nerve elicited efficient (73.2 +/- 10.7%) voiding. Blocking the pudendal nerves bilaterally produced voiding efficiency (82.5 +/- 4.8%) comparable to the efficiency during voidings induced by bladder distension in spinal intact cats, indicating that the external urethral sphincter (EUS) contraction was caused not only by direct activation of the pudendal efferent fibers, but also by spinal reflex activation of the EUS through the contralateral pudendal nerve. The maximal bladder pressure and average flow rate induced by stimulation and bilateral pudendal nerve block in chronic SCI cats were also comparable to those in spinal intact cats. CONCLUSIONS: This study shows that after the spinal cord is chronically isolated from the pontine micturition center, bladder distension evokes a transient, inefficient voiding reflex, whereas stimulation of somatic afferent fibers evokes a strong, long duration, spinal bladder reflex that elicits efficient voiding when combined with blockade of somatic efferent fibers in the pudendal nerves.