PhysMedRehabilClinNAm 15(2004)749–772 The role of acupuncture in pain management Joseph F. Audette, MA, MDa,b,*, Angela H. Ryan, MDa,b aDepartmentofPhysicalMedicineandRehabilitation,HarvardMedicalSchool, Boston,MA,USA bSpauldingRehabilitationHospital,125NashuaStreet,Boston,MA02114,USA Acupuncturehasbeenusedasatherapeuticmodalityformorethan3000 years, but it is only since the 1970s that a greater understanding of the underlying mechanisms of acupuncture analgesia (AA)has developed. This growth in understanding of AA has paralleled the scientific advances made in uncovering the physiology of pain perception. Similar to many ancient healing traditions, acupuncture has accumulated a wealth of anecdotal experiences documenting its clinical effectiveness for a variety of problems. Although acupuncture has survived the test of time, medicine today demands more, and ultimately acupuncture must withstand the scrutiny of science if it is to become a mainstay in the treatment of pain. Given the explosionof interest within the scientific andclinicalmedical communityin acupuncture, it is fortunate that a substantial body of evidence to support theefficacyofacupunctureexists,incontrasttomanyothercomplementary andalternativemedicine(CAM)therapies.Thisarticleoutlinesunderstand- ing to date of the underlying physiologic mechanisms of AA, then reviews current use of acupuncture in pain management for some common musculoskeletal conditions seen in clinical practice. Philosophy of acupuncture Employed as one of many therapeutic interventions in Traditional Chinese Medicine, acupuncture traditionally was believed to work by maintainingandbalancingtheflowofQiinthehumanbody.Qiisaconcept that is difficult to translate into English, but it commonly is equated with ‘‘vitalenergy’’andhasbeensubsumedunderthevariousWesterntraditions *Correspondingauthor. E-mailaddress:[email protected](J.F.Audette). 1047-9651/04/$-seefrontmatter(cid:1)2004ElsevierInc.Allrightsreserved. doi:10.1016/j.pmr.2004.03.009 750 J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 of vitalism. The concept of Qi is much more complex and broad reaching, however, and interconnects living and inanimate objects in nature and the universe.QiisessentiallyanenergeticconceptthatispostulatedbyChinese philosophy as a tangible force that allows energy transfer, movement, growth,anddevelopmenttooccur.Tomaintainphysicalandmentalhealth, theflowofQimuststayfluidandinbalancemacroscopically,asindividuals relate to their environment, and microscopically, as organ functions interact.AblockageintheflowofQicancauseanimbalanceandeventually manifest as disease. AccordingtoTraditionalChineseMedicine,individualscaninfluencethis balanceofQiinternally,byanalyzingtheflowofQialongdefinedpathways onthesurfaceofthebodyinasetofchannelscalledmeridians(Fig.1).The meridians all are connected to each other and to all the internal organs in complex patterns. Treatment involves first correctly identifying the internal and external imbalances, then, by inserting needles into appropriate points along the meridians, helping to realign Qi flow in the body to restore in- ternal homeostasis [1,2]. Pain and analgesia From a modern scientific perspective, the Chinese notion of Qi and meridians has not been documented with current technologies. The basic premiseofacupuncture,insimplifiedterms,isthatstimulationatonesiteon the body has an effect on another, more distant site. Perhaps at a more profound level, a second premise of acupuncture theory is that internal pathology can be diagnosed and treated with surface evaluation and Gall Urinary Governing v. bladder Pericardium bladder Heart Stomach Lung 1( )3 1( )1 ( )9 ( )7 ( )5 ( )3 ( )1 1( )4 1( )2 1( )0 ( )8 ( )6 ( )4 ( )2 Conception v. Liver 3 Warmers Kidney Small Spleen Large intestine intestine Fig.1. Acupuncturemeridians. J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 751 stimulation by taking advantage of somatovisceral and viscerosomatic reflexes. The substantiation of these hypotheses has been made more plausible with the growth in understanding of the neuroanatomy of pain processing (discussed subsequently). First, the physiology of pain as it is currently understood is outlined. Second, the evidence of how acupuncture alters the transmission and perception of pain is presented. Finally, the clinical evidence for the role of acupuncture in treating various pain syndromes is reviewed. Pain physiology The physiology of pain perception and modulation is a sophisticated, multilayered system that is activated with injury under normal circum- stances. This activation leads to a complex series of events that includes signal processing along neural pathways, immunologic and hormonal releases, and psychobehavioral responses. The current thinking underlying pain perception and inhibition accepts a dynamic, malleable, and complex set of interacting neurons, with gene regulation and expression producing a variety of neuropeptides and cytokines at the peripheral nervous system andcentralnervoussystem(CNS)level.Therecognitionoftheplasticityof the nervous system has revolutionized the understanding of pain, especially chronic pain. After reviewing the neural pathways involved with pain modulation, the authors explain how acupuncture is believed to influence each of these domains. Peripheral nervous system The neuroanatomy of nociception can be organized into three distinct but connected domains: the peripheral sensory apparatus, the spinal cord, and the brain. Starting in the periphery, small-fiber sensory axons that respond to various types of noxious input are called nociceptors. There are two main nerve types that carry pain and temperature information—the small, unmyelinated C fibers and the larger, thinly myelinated Ad fibers. In theskin,theCfibers,whichconductmoreslowlythantheAdfibersandare considered high-threshold nociceptors, carry more diffuse and dull pain information and require higher levels of stimulation and tissue damage to activate.TheAdfiberscarrythesensationofsharppainandareconsidered low-threshold nociceptors, providing more discriminative information. Similar sensory afferents are found in muscle; however, in muscle, both fibertypesconveyadullachingsensationwhenactivated,incontrasttoskin nociceptors (Fig. 2). In addition to nociceptors responding to mechanical pain and temperature input, the release of chemical substances in tissues, suchashistamine,protons,bradykinin,vasoactivepolypeptide,andawhole array of others, can lead to nociceptor activation. 752 J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 Dorsal root Descending tracts Ventrolateral column A-α,γ Anterior root A-δ, C A-α,β Skeletal muscle Bare endings Meissner's Tendon corpuscles bundle Pacinian Muscle corpuscles spindle Fig.2. Afferentsensoryfibersenterthespinalcordviathedorsalrootganglion.Small,thinly myelinated and unmyelinated fibers (Ad and C) enter the dorsal horn and distribute in the laminaasindicated. Spinal cord As with all afferent information, the sensory nerves from the skin enter thedorsalsideofthespinalcord.Thecellbodiesofthesesensorynervesare in the dorsal route ganglion. When in the spinal cord, the fibers synapse in laminae I through IV ofthe dorsal horn gray matter, with laminae I and II receivingthebulkofthenociceptiveinputfromtheskin.Beforeenteringthe dorsal horn, the primary sensory afferents branch and commonly ascend and descend multiple segmental levels before ending in a synapse with interneurons and second-order neurons. Most of the second-order neurons cross the midline and travel to the brain on the contralateral side from the site of nociception. Interneurons play a role in pain inhibition. The main pathways involved are the spinothalamic and the spinoreticular tracts. Together, these tracts make up the anterolateral system of the CNS [3]. Brain In the brain, multiple areas have been implicated as having some role in painperceptionandregulation.Spinalcordpathwayssynapsedirectlyinthe J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 753 brainstem reticular formation, the amygdala, the hypothalamus, and the thalamus. At a higher level, the somatosensory cortex and higher cognitive brainregionsalsoareactivated,althoughnotdirectly[4].Thesehigherlevels contributetotheaffectiveandemotionalaspectsofpainsensation.Research has shown that stimulation of many nociceptors in the periphery are not transmitted uniformly to the somatosensory cortex, but are transmitted to other areas of the brain, such as the frontal cortex, subcortical areas in- volved in the limbic system, and the hypothalamus [5]. Muscle pain physiology The nociceptive information carried from muscles takes a slightly different route than that carried from the skin. Outlining the different pathwaysisimportantnotonlyinunderstandingtheexperienceofpain,but also in understanding the possible neural mechanisms of acupuncture. Acupuncturestimulationtypicallyinvolvesneedlepenetrationtothemuscle and deeper connective tissue structures than the skin level. Similar to nociceptive information from the skin, low-threshold and high-threshold small fibers, named group III and IV fibers, travel to the dorsal horn of the spinal tract and correspond to cutaneous Ad and C fibers, respectively. Thesefiberssynapseinthesamelaminaascutaneousinformation,buthave a higher representation in laminae IV and V. In laminae IV and V, wide dynamic range (WDR) second-order neurons reside. In contrast to second- orderneuronsinlaminaeIandII,whichhaveanon-offresponsetosensory input,WDRneuronshaveagradedresponsetosensoryinput.Toillustrate, normal stretch of a muscle stimulates low-frequency output of the WDR neurons, which should not be perceived as painful, whereas high-frequency input into the dorsal horn, such as after pathologic stretch and injury of a muscle, causes high-frequency output and pain. Under pathologic con- ditions, wind-up can occur in the second-order WDR neurons found in laminaeIVandV,andlow-frequencyinputcanleadtohigh-frequencyout- put. This heightened firing pattern of neurons in the CNS is believed to be oneofthefactorsinvolvedwithchronicpain[6].Anotheruniquefeatureof WDR second-order neurons is that there is convergence of sensory information from the afferents of skin, muscle, viscera, tendons, and joints [7].Thisconvergenceofsensoryinformationopensthedoortounderstand- ing how sensory stimulation of muscles with acupuncture can influence other visceral and somatic structures. Chronic pain Neuroplasticity of the peripheral nervous system and CNS lies behind much of the current research and theory of chronic pain. Changes in intracellular signal transduction, gene expression, receptor and ion channel density,anddepolarizationthresholdscontributetoaperipheralsensitization 754 J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 and central wind-up phenomenon in the pain pathway. Sensitization in the periphery can occur directly at the small-fiber, nociceptor terminals by repeatedhigh-frequencystimulationorbytheprolongedpresenceofsignaling molecules that signify ‘‘damage’’ or ‘‘inflammation.’’ These signaling mole- culesincludesubstanceP,serotonin,bradykinin,epinephrine,adenosine,and nervegrowthfactor,amongothers[8]. Thechangesinthedorsalhornofthespinalcordinresponsetopersistent nociceptive input invoke the wind-up phenomenon, as mentioned earlier. Adopting the theory of long-term potentiation in the hippocampus as the neuroplastic changes responsible for the learning and retention of new informationtoformmemories,asimilartheoryishypothesizedinthespinal cord for the ‘‘learning’’ of chronic pain. Long-term potentiation represents a long-lasting change in neuronal synapses as a result of high-frequency input. In the context of pain, nociceptive input from a prolonged noxious stimulusmayleadtoneuroplasticchangesinthespinalcord,whichresultin a ‘‘learned’’ perception of pain, even when the noxious input is no longer present. As discussed later, acupuncture may have a role in reversing some of these neuroplastic changes. Pain inhibition At the peripheral and spinal cord level, the role of pain inhibition originally was described via the gate control theory. Although the gate control theory of pain as introduced by Melzack and Wall [9] in 1965 does not fully explain pain inhibition, some of the segmental analgesic effects of AA do invoke this system. It is a useful and applicable theory, especially whenitcomestounderstandingsomeofthetheoriesofAA[10].According tothegatecontroltheory,large,myelinatedAbsensoryafferentssynapseon inhibitoryinterneuronsinthedorsalhorn,whichwhenactivatedcaninhibit the activation of second-order neurons that receive input from the smaller nociceptor fibers (Fig. 3). Since the time of Melzack and Wall, theories of pain perception and inhibition have focused more on a biochemical level involving gene regulation, receptor expression, and depolarization thresholds. On the peripheral level, central pathologic changes and peripheral injury can lead to sensitization of the nociceptor terminal. Small-fiber, unmyelinated afferents have been found to have retrograde, neurosecretory properties similar to sympathetic fibers. Under pathologic conditions, substance P, a neuropeptide that normally acts centrally, can be secreted peripherally at thenociceptorterminal.ThisperipheralsecretionofsubstancePcanleadto a cascade of events, including the degranulation of local mast cells, which can cause a sensitizing chemical soup with molecules such as serotonin, bradykinin, epinephrine, adenosine, and nerve growth factor (Fig. 4). This process of peripheral sensitization has the consequence of lowering the thresholdbywhichtheperipheralnociceptorfiresinresponsetostimulation J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 755 Central control To higher centers Gate-Control System L Action SG T system S Inhibitory synapse Excitatory synapse Fig.3. Gatecontroltheory.(ModifiedfromMenseS,SimonsDG.Centralpainandcentrally modifiedpain.In:Musclepain:understandingitsnature,diagnosisandtreatment.Philadelphia: LippincottWilliams&Wilkins;2001.p.176;withpermission.) andcanleadtotheclinicalphenomenonofhyperalgesia.Inaddition,ithas beenfoundinanimalmodelsthatacupuncturepointshaveelevatedlevelsof substance P, suggesting a mechanism as to why needle stimulation at these points may be activating sensitized peripheral nociceptors [11]. Anticlromic stimulation Dorsal Nociceptor horn cell Signal Signal Mast cell CGRP Substance P Serotonin NO,Bradykinin Histamine Vasoactive Intestinal Peptide Edema Blood vessel Fig.4. Diagramillustratestheneurosecretoryactionsofperipheralnociceptorsandtherolethe release of substance P plays in causing mast cell degranulation and peripheral sensitization. CGRP,calcitoningene–relatedpeptide;NO,nitricoxide. 756 J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 Atthelevelofthespinalcord,theinterneurons,whichreceivenociceptive and non-nociceptive afferent information, act on WDR and other second- orderneuronstoalterpainperception.Presynapticinhibition,whichactsto hyperpolarize presynaptic pathways and reduce their activation of pain tracts, is often mediated by c-aminobutyric acid. Interneurons also act postsynaptically by inhibiting signal transmission to second-order neurons. Postsynaptic inhibition is mediated primarily by opioids and glycine. It is also at the postsynaptic level that supraspinal signals from the descending pathways exert their influence. These signals are mediated by, among other things, norepinephrine, serotonin, and acetylcholine [12]. Inhibitionofpainatthelevelofthebrainhascometobeunderstoodwell through the role of endogenous opioids and the descending pain inhibitory system. Endogenous opioids, such as endorphins, dynorphins, and enke- phalins,arepeptidesthatactintheCNStomodulatepain.Thereareafew well-identified areas of the brain and spinal cord that are known to be sites of opioid action: the hypothalamus, limbic system, basal ganglia and periaqueductalgrayarea,nucleusraphemagnus,reticularactivatingsystem, andspinalcordinthedorsalhorn.Thedescendinginhibitorysystemtravels from the hypothalamus and periaqueductal gray, through the medulla (wherethenucleusraphemagnusandreticularactivatingsystemare)tothe dorsal horn of the spinal cord, where inhibition of the afferent nociceptive information occurs (Fig. 5). As discussed later, acupuncture research has shown that it has a role in activating this descending inhibitory system. Mechanism of acupuncture analgesia Acupuncture and the peripheral nervous system IthasbeenpossibletoexplainsomeoftheTraditionalChineseMedicine experiencesofacupuncture,suchasthesensationofDeQiandthemeridian system, by more modern understanding of anatomy and physiology. Traditionally, Chinese acupuncture needle manipulation at specified points is verified to be accurate when the recipient experiences a De Qi sensation, which is described as a deep aching sensation. It now is believed that this sensation is a sign of the activation of group III and IV fibers in skeletal muscle. An analogy has been drawn in tying the physiologic benefits of sustainedphysicalexercise andthestimulationofthesame muscleafferents that are activated with acupuncture stimulation [13]. As mentioned earlier, the distribution of these muscle sensory afferents to the dorsal horn of the spinalcordmayplayanimportantroleintheobservedphysiologiceffectof acupuncture stimulation, especially if these afferents are sensitized, as evidenced by elevated substance P found in animal models of acupuncture points. Additionally the correlation between acupuncture points and myofascial trigger points has been mapped [14]. Keeping in mind the differences in J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 757 To thalamus From hypothalamus GABA? Enkephalinergic neuron PAG Inhibitory synapse Excitatory synapse EAA/NT? Rostral NRM medulla NE 5-HT SP? Spinal cord Nociceptive input Fig.5. Thedescendingpainmodulationsystem.Theperiaqueductalgrayarea(PAG)isinthe mesencephalonandisamajorcontrolareaforthedescendingsystem.Therostralmedullalevel is where the nucleus raphe magnus (NRM) and the reticular activating system (RAS) are locatedandiswheremultipledescendingantinociceptivestracksoriginate.Cellsinthesecenters areactivatedbyexcitatoryaminoacids(EAA),suchasglutamateandaspartateandpossibly neurotensin(NT).Fromhere,thedescendingtracksenterthedorsalhornofthespinalcord, andinhibitionismediatedmainlybynorepinephrine(NE)andserotonin(5-hydroxytryptamine [5-HT]).(ModifiedfromMenseS, SimonsDG.Centralpainandcentrally modified pain.In: Muscle pain: understanding its nature, diagnosis and treatment. Philadelphia: Lippincott Williams&Wilkins;2001.p.177;withpermission.) muscle and skin pain pathways previously outlined, stimulation of muscle tissue (as in trigger point injections and acupuncture) not only may have a pain-inhibitory effect, but also may influence visceral structures and remote somatic structures because of sensory convergence on the same WDR second-order neurons. Acupuncture and descending pain inhibition Themostwell-delineatedeffectthatacupuncturehasonpaininhibitionis thewayitinfluencesthedescendinginhibitorypainsystem.Inthelate1970s and early 1980s, many studies investigated the relationship between acupunctureandpaininhibition.Thestudiesmeasuredeitheropioidactivity in the brain in relationship to AA or a reduction in AA with the administration of opioid antagonists, such as naloxone or naltrexone, and compared the analgesic effects of acupuncture with those of morphine. 758 J.F.Audette,A.H.Ryan/PhysMedRehabilClinNAm15(2004)749–772 Acupuncture has been shown to influence pain perception by modulating theactivityofkeysubcorticalandbrainstemsitesalongthedescendingpain modulating system pathway [15]. Given the variety of neurotransmitters discussed so far involved in the peripheral sensitizing soup and the wind-up phenomenon, it is not surprising that there are potentially many nonopioid mechanisms of analgesia that may be involved. As just one example, low-intensity and high-frequency electrical stimulation has a faster onset of action but does not have as prolonged an effect as high-intensity and low-frequency stimulation. The former is thought to be serotoninergic mediated and the latter opioid mediated [16]. Although the demonstration that endogenous opioids and other neuro- transmitterscanbereleasedconsistentlyinanimalandhumanexperimental models has been an important step in verifying that AA has a physiologic basis, there continues to be debate about whether this effect is sufficient to explain the observed clinical benefits. One of the problems is that such humoral effects are nonspecific and short-lived and cannot explain why certaintreatmentmethodsforparticularconditionswouldhaveasustained orpermanentdisease-modifyingresult.Thechemicalreleasesobservedwith electroacupuncture (EA) and manual acupuncture (AP) may just be an epiphenomenon, indicating that there has been an influence on the CNS without fully comprehending what the actual homeostatic influence has been. Onetheorythatmayhelptoexplainbetterthelong-termeffectofEAand APisthatbystimulatingperipheralsensoryafferentsoftheskinandmuscle, sustained changes occur in the CNS via central neuromodulation. A fundamental concept that has emerged is that sustained nociceptive input can have profound effects on the CNS causing pathologic neuroplastic changes. Continuing along this line of argument, in contrast to trans- cutaneous electrical nerve stimulation (TENS), AP and EA do rely on a more ‘‘painful stimulation’’ of the peripheral nervous system. In effect, through controlled stimulation of peripheral nociceptors, acupuncture may be causing a reverse neuroplasticity in the CNS. AcluetotheneuroplasticchangesthatmaybeoccurringintheCNSwith EP and AP can be found in the literature looking at c-Fos expression. The expression of the gene c-Fos in the CNS occurs in cells believed to be activated after noxious peripheral stimulation. The Fos protein is the nuclear product of the immediate-early gene c-Fos and couples transient intracellularsignals tolong-term changes ingeneexpressionandisbelieved to herald neuroplastic changes in the CNS [17]. A body of literature has looked at c-Fos expression in the spinal cord and brain in relation to acupuncture. Acupuncture has been shown to suppress c-Fos expression in the spinal cord and the brain after noxious peripheral stimulation, suggesting a possible neuromodulatory mechanism that is independent of endogenous opioid release [18].