The Spine Journal 8 (2008) 21–27

Intervention Review Articles

Evidence-informed management of chronic lowback pain with adjunctive analgesics

Victor Chang, MDa,b, Peter Gonzalez, MDa,b, Venu Akuthota, MDa,b,*aThe Spine Center at University of Colorado Hospital, CO, USA

bDepartment of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, CO, USA

Received 1 October 2007; accepted 15 October 2007

Abstract EDITORS’ PREFACE: The management of chronic low back pain (CLBP) has proven very chal-lenging in North America, as evidenced by its mounting socioeconomic burden. Choosing amongavailable nonsurgical therapies can be overwhelming for many stakeholders, including patients,health providers, policy makers, and third-party payers. Although all parties share a common goaland wish to use limited health-care resources to support interventions most likely to result in clin-ically meaningful improvements, there is often uncertainty about the most appropriate interventionfor a particular patient. To help understand and evaluate the various commonly used nonsurgicalapproaches to CLBP, the North American Spine Society has sponsored this special focus issueof The Spine Journal, titled Evidence-Informed Management of Chronic Low Back Pain WithoutSurgery. Articles in this special focus issue were contributed by leading spine practitioners and re-searchers, who were invited to summarize the best available evidence for a particular interventionand encouraged to make this information accessible to nonexperts. Each of the articles contains fivesections (description, theory, evidence of efficacy, harms, and summary) with common subheadingsto facilitate comparison across the 24 different interventions profiled in this special focus issue,blending narrative and systematic review methodology as deemed appropriate by the authors. Itis hoped that articles in this special focus issue will be informative and aid in decision makingfor the many stakeholders evaluating nonsurgical interventions for CLBP. � 2008 Elsevier Inc.All rights reserved.

Keywords: Chronic low back pain; Socioeconomic; Nonsurgical therapies; Neuropathic medications

Description

Terminology

Adjunctive analgesics (also known as adjuvant pain medi-cations) refer to classes of drugs that can be used for pain reliefin chronic low back pain (CLBP) other than the more com-monly used drug classes such as nonsteroidal anti-inflamma-tory drugs (NSAIDs), muscle relaxants, simple analgesics,or opioids; the use of those classes of drugs for CLBP isreviewed elsewhere in this supplement.

FDA device/drug status: not applicable. Non-FDA approved indica-

tions for medications are discussed.

Nothing of value received from a commercial entity related to this

manuscript.

* Corresponding author. Anschutz Outpatient Pavilion, Mail Stop

F493, P.O. Box 6508, Aurora, CO 80045, USA. Tel.: (303) 725-7317;

fax: (720) 848-2019.

E-mail address: venu.akuthota@uchsc.edu (V. Akuthota)

1529-9430/08/$ – see front matter � 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.spinee.2007.10.006

History

In individuals progressing from acute low back pain toCLBP, adjunctive analgesics appear to have grown in pop-ularity in recent years given that traditional analgesics arenot always able to achieve complete pain relief in allpatients. The use of adjunctive analgesics is based on theetiology of CLBP, which can be divided into nocioceptive(pain stemming from tissue injury) and neuropathic (painstemming from nerve injury). Most CLBP is considerednocioceptive but may nevertheless refer pain to the leg.True neuropathic radicular pain stems from nerve root in-jury or irritation. This distinction is important to avoidthe indiscriminate use of adjunctive analgesics for nocio-ceptive pain, when they have a much stronger theoreticalbasis for use in neuropathic pain. See Table 1 for a compar-ison of nocioceptive/referred pain and neuropathic/radicularpain characteristics.

22 V. Chang et al. / The Spine Journal 8 (2008) 21–27

Subtypes

Adjunctive pain medications include classes of drugssuch as tricyclic antidepressants (TCAs), selective seroto-nin reuptake inhibitors (SSRIs), serotonin-norepinephrinereuptake inhibitors (SNRIs), and antiepileptic drugs, all ofwhich may be used for CLBP. Each class of drug includesseveral medications and is summarized below.

Practitioner, setting, and availability

Adjunctive analgesics generally require a prescriptionand can be dispensed by any physician with a medical li-cense. Pain management specialists are perhaps best suitedto prescribe and monitor use of adjunctive analgesic medi-cations for CLBP. This intervention is widely available ina variety of settings throughout the United States, includingprivate practices and hospitals.

Reimbursement

Individual insurance carriers vary in their formulary cov-erage of newer medications or newer indications for estab-lished medication (eg, depression). Some may require priorauthorization, failure of a cheaper medication, or medicaljustification for using a more expensive medication withinthe same class or category. In general, these medicationsare widely reimbursed by third-party payers.

Regulatory status

The common adjunctive analgesics discussed in thisreview are approved by the US Food and Drug Administra-tion (FDA) for other indications and are thus used off-labelfor CLBP.

Theory

Mechanism of action

Adjunctive pain medications work at different parts ofthe chronic pain pathway [1]. Pain is activated througha veritable cornucopia of peripheral receptors, often pro-ducing an inflammatory soup of mediators (eg, bradykinin,leukotrienes, substance P). Agents such as capsaicin cream

Table 1

Characteristics of radicular versus referred pain

Type

Neuropathic/radicular

pain

Nocioceptive/referred

pain

Quality Numbness, tingling,

burning

Dull, achy

Location Discrete band

of pain

Vague pain

Leg involvement Pain often above leg Pain often below leg

Neurological deficit Occasional None

Dural tension Positive Negative

and anti-inflammatory medications work at this level byblocking the activity of specific inflammatory pain enzymes(eg, cyclo-oxygenase). With chronic pain, a windup phe-nomenon occurs with the dorsal horn having increased ac-tivity of N-methyl-D-aspartate receptors. Windup furtheroccurs by activation of voltage-gated calcium channels,which can be blocked by gabapentin and pregabalin. Cen-tral sensitization via modulation of the spinal cord eventu-ally occurs in chronic pain states. Descending inhibition ofthe pain pathway is depressed at the spinal cord level. Olderantidepressants (eg, TCAs) and newer, mixed-agent antide-pressants (eg, SNRIs) are thought to work by enhancing thisdescending inhibition by increasing levels of the neuro-transmitters serotonin and norepinephrine. Other agents(eg, carbamazepine) work by making nerves less excitable(preventing ectopic impulses) by blocking voltage-gatedsodium channels. Newer generation adjunctive analgesicsare touted to work at multiple levels of the pain pathway.

Tricyclic antidepressants

TCAs are theorized to provide neuropathic pain reliefvia serotonergic and noradrenergic pathways, and perhapsnerve membrane stabilization [2]. The ratio of serotonergicto noradrenergic action may differ based on the individualTCA. There are several types of TCAs, and classificationhas varied over time. Initially, a structural algorithm wasused (eg, tertiary vs. secondary amine TCAs). However,classification based on a structural basis lacks clinical util-ity, especially with the focus on mechanisms of action ofthe TCAs and the development of newer, non-TCA agents.Another commonly used classification system for TCAsinvolves associated side effects, as noted below. As the nor-adrenergic TCAs are usually more tolerable than the bal-anced reuptake TCAs, dosage policy may be particularlyimportant in this comparison [3]. In comparing in vivoand in vitro effects of TCAs, TCAs demonstrate balancedinhibition of serotonin and noradrenaline reuptake in vitroto variable degrees, but in vivo, as TCAs are metabolizedto secondary amines, they may primarily affect noradrena-line reuptake [4].

Selective serotonin reuptake inhibitors

SSRIs are thought to contribute to clinical improvementin CLBP by addressing emotional disturbances that may re-late to neuropathic pain rather than through neuropathicpain pathways.

Serotonin-norepinephrine reuptake inhibitors

SNRIs affect both serotonergic and noradrenergic path-ways and include venlafaxine (Effexor), duloxetine (Cym-balta), and milnacipran (Ixel, currently not available inthe United States). Another medication, mirtazapine (Re-meron), has been referred to as a dual-action ‘‘noradrener-gic and specific serotonergic drug,’’ but mirtazapine has not

23V. Chang et al. / The Spine Journal 8 (2008) 21–27

demonstrated significant serotonergic effects in humans [5].For venlafaxine, the balance between serotonergic and nor-adrenergic reuptake inhibition relates to dosage, as lowerdoses primarily affect serotonin pathways, and higher dosesaffect noradrenaline reuptake [6]. Duloxetine affects seroto-nin and noradrenaline pathways in a manner that is notdependent on dosage [7].

Antiepileptics

The use of antiepileptic medications as adjunctive anal-gesics for CLBP likely arose from their FDA approval forneuropathic pain conditions such as postherpetic neuropa-thy (PHN) and diabetic peripheral neuropathy (DPN).These medications are postulated to work through variousmechanisms of action according to the subtypes describedbelow (Table 2).

First generation antiepileptics

Carbamazepine is thought to act through inhibition ofvoltage-gated sodium channels and may have a stabilizing ef-fect on neuronal membranes. Carbamazepine is titrated from100 to 200 mg per day to a maximum dose of 1,200 mg dailyand requires meticulous monitoring of blood levels becauseof a narrow therapeutic window.

Second generation antiepileptics

Until recently, the mechanism of gabapentin was un-known. Gabapentin is an alpha2-delta ligand and is structur-ally related to gamma amino butyric acid (GABA), actingat voltage-gated calcium channels. Gabapentin inhibits ex-citatory neurotransmitter release, though it does not binddirectly to GABA receptors and is not converted to GABA.Gabapentin dosing requires a slow titration to therapeuticlevels, starting at 100 to 300 mg daily and titrating to a dailymaximum of 3,600 mg divided into three or four doses.

Third generation antiepileptics

Pregabalin is an alpha2-delta ligand and an analog ofGABA that does not bind GABA, nor is it converted to

Table 2

Mechanisms of action for different antiepileptics

Medication Mechanism of action

Carbamazepine Inhibits voltage-gated Naþþ channels

Gabapentin Acts on voltage-gated Caþþ channels

Lamotrigine Acts at Naþþ and N-type Caþþ channels

Oxcarbazepine Blocks voltage-gated Naþþ channelsMay affect Caþþ and Kþþ conductance

Phenytoin Inhibits voltage-gated Naþþ channels

Pregabalin Acts on voltage-gated Caþþ channels

Topiramate Acts on voltage-gated Naþþ channelsPotentiates gamma amino butyric acid transmissionBlocks AMPA/glutamate transmission

AMPA5a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid.

GABA. It acts at voltage-gated calcium channels like gaba-pentin. Dosing of pregabalin requires a titration to 300 mgdaily with starting dosages of 50 mg three times a day or75 mg twice a day. It does not require a prolonged titrationbecause of increased bioavailability and linear pharmacoki-netics. Topiramate is thought to block voltage-dependentsodium channels, potentiate GABA transmission, and in-hibit excitatory neurotransmission. At doses of 300 mg/day,topiramate has been reported to alleviate CLBP by re-ducing pain symptoms and improving mood and quality oflife [8].

Lamotrigine’s proposed anti-nocioceptive effects arethrough sodium blockade and neural membrane stabiliza-tion, as well as through inhibiting the presynaptic releaseof glutamate.

Indications

Over the years, many antidepressants have been investi-gated for the treatment of neuropathic pain. However, thereare few studies focusing on the use of antidepressants forCLBP and the majority of the literature relates to other neu-ropathic pain conditions including painful polyneuropathy(PPN), PHN, central poststroke pain, and postmastectomypain.

No antiepileptic medications are FDA approved forCLBP, nor are there adequate clinical trials to support theuse of these medications for this purpose. However, manyantiepileptic medications are used off-label in the manage-ment of primarily neuropathic or radicular pain states, suchas lumbar and cervical nerve root lesions and spinalstenosis.

Carbamazepine (Tegretol) is approved for neuropathicpain states such as trigeminal and glosso-pharyngeal neu-ralgia. Gabapentin (Neurontin) is approved for PHN [9],though other studies have showed efficacy in DPN [10],and it is approved as an adjunctive medication for partialseizures. Pregabalin (Lyrica) recently received FDA ap-proval for treatment of DPN and PHN [11]; it is also ap-proved for neuropathic pain in Europe. Like gabapentin,it is approved as an adjunctive medication for partial sei-zures. No studies have been done specifically evaluatingpregabalin’s role in CLBP. Topiramate (Topamax) is an an-tiepileptic medication FDA approved for partial/general-ized tonic-clonic seizures. Lamotrigine (Lamictal) has noFDA approval for neuropathic pain states, but studies haveindicated efficacy in trigeminal neuralgia [12] and DPN[13]. Oxcarbazepine (Trileptal) is not approved by theFDA for any pain states but studies have demonstratedsome efficacy in trigeminal neuralgia, PHN, and DPN [14].

Phenytoin (Dilantin) carries no FDA approval for neuro-pathic pain, but has reported efficacy for trigeminal neuralgia[15]. Other antiepileptics such as valproic acid, felbamate,and zonigran lack FDA approval and lack any significantclinical evidence supporting their usage for treatment ofneuropathic pain.

24 V. Chang et al. / The Spine Journal 8 (2008) 21–27

Evidence of efficacy

Systematic reviews

Chronic low back painPrevious reviews have reached different conclusions re-

garding the efficacy of antidepressants in low back pain[16]. A review of six studies before 1992 concluded thatthere was insufficient evidence to recommend their use[17]. A review of four studies in 1997 also failed to findsupporting evidence of clinical benefit [18]. A meta-analy-sis in 2001, reviewing nine previous studies [19], and an-other review in 2004, reviewing seven previous studies[20], concluded that antidepressants were more effectivethan placebo to treat CLBP. However, the meta-analysiswas criticized for failing to distinguish effectiveness of dif-ferent classes of antidepressants, and also for including twostudies that did not distinguish between neck and back pain[16]. Similarly, the 2004 review did not distinguish the dif-ferent antidepressants used. A review in 2003 concludedthat based on a small number of studies, TCAs and tetracy-clic antidepressants produced moderate symptom reduc-tions for patients with CLBP independent of depressionstatus [16]. Lastly, there was conflicting evidence as towhether antidepressants improved the functional status ofpatients with CLBP. That review initially evaluated 22 priortrials of antidepressants for the treatment of back pain, butonly seven met inclusion criteria, as the others lacked pla-cebo control, included neck and low back pain patients, orused parenteral routes.

SSRIs have failed to demonstrate efficacy in the treat-ment of CLBP [16,21] and various neuropathic pain condi-tions [22–26] As such, other than addressing emotionaldisturbances that may relate to neuropathic pain, the med-ical literature does not support the use of SSRIs to primarilyaddress CLBP or neuropathic pain itself.

Neuropathic pain conditionsFor neuropathic pain conditions, TCAs have been investi-

gated more extensively than SSRIs, SNRIs, and antiepilep-tics. Neuropathic pain relief appears to occur independentof any antidepressant effect [23]. Notably, antidepressant ef-fects of TCAs may take several weeks while improvement ofpain may occur substantially sooner. Titration to an effectivedose may take several weeks such that individuals tolerateside effects of TCAs.

In a systematic review of antidepressants in neuropathicpain conditions, 30% of patients given antidepressants hadmore than 50% pain relief [22]. The number needed to treat(NNT), defined as the number of patients needed to treatwith a certain drug to obtain one patient with at least50% pain relief, has been used to evaluate the pain-reliev-ing effects of numerous medications used for neuropathicpain [3]. The NNT for TCAs was 2.6 (2.2–3.3) when com-paring several different studies involving several differentneuropathic pain conditions [3]. However, from a more

recent review, significant variation in NNT values withinTCAs was noted, which may be related to the differencesin neuropathic pain diagnoses and the use of drug-levelmeasurements to obtain optimal dosing [23]. NNT hasnot been defined for CLBP or radicular pain conditions.

Comparing the individual TCAs among each other isdifficult, as dosages in some trials were titrated to perceivedbenefits and side effects, whereas other studies targeted op-timal plasma drug concentration. In comparing the TCAswith balanced reuptake of serotonin and noradrenaline tothe TCAs with relatively selective noradrenaline reuptakein the PPN population, there is a trend toward better effectwith the balanced TCAs (NNT 2.1) compared with the nor-adrenergic TCAs (NNT 2.5) [23,24]. In PHN, a similartrend has been noted (balanced TCA NNT 2.5 vs. noradren-ergic TCA NNT 3.1) [23]. Although the trend may show fa-vorability toward the balanced TCAs, other issues such asside-effect profile and secondary symptoms (eg, insomnia)need to be considered.

Randomized controlled trialsSeveral studies have evaluated venlafaxine for neuro-

pathic pain conditions. In a comparison of venlafaxine(a SNRI) to imipramine (a TCA), patients with PPN had im-provement of symptoms with either medication comparedwith placebo, though the NNT for venlafaxine (5.2) washigher than for imipramine (2.7) [27,28]. In a study evalu-ating neuropathic pain after breast cancer, venlafaxine wascompared with placebo, noting improvement of averagepain relief and maximum pain intensity, though anxietyand depression were not affected [29]. However, dosageof venlafaxine in this study was only 37.5 or 75 mg daily,raising questions as to whether a higher dose would havebeen more efficacious, though it may also have causedhigher dropout rates from side effects. In a larger studyinvolving 244 patients with DPN, higher dosages of venla-faxine (150–225 mg per day) effectively relieved pain com-pared with placebo, with the NNT being 4.5. However,seven patients on venlafaxine developed clinically impor-tant EKG changes [30].

Several double-blinded, placebo-controlled RCTs ofduloxetine have shown improvement of major depressivedisorder [2,31–33]. In addition, these studies also demon-strated improvement of visual analog scale ratings of phys-ical symptoms associated with depression including overallpain and back pain. These findings, along with the existingevidence of effectiveness of treating certain neuropathicpain conditions with serotonergic and noradrenergic reup-take inhibitors, prompted further investigation of duloxetinefor use in patients with diabetic peripheral neuropathic pain(DPNP) [34]. The FDA has approved duloxetine for DPNPbased on RCTs by Raskin, Goldstein, Wenicke, et al. [34–36]. The anticonvulsant pregabalin has also been FDA ap-proved for DPNP. Dosing in these studies ranged from 60to 120 mg daily. In comparing 60 mg daily versus 60 mgtwice daily, equivalent analgesia was demonstrated, though

25V. Chang et al. / The Spine Journal 8 (2008) 21–27

the use of acetaminophen for breakthrough pain was less inthe 60 mg twice daily group. Goldstein et al. have sug-gested that higher dosage may be more helpful for patientsdescribing shooting, stabbing, sharp, hot burning, and split-ting pain [34]. The pain-relieving effect of duloxetine ap-pears to be independent of any mood improvement effect.

AntiepilepticsThere is limited evidence directly evaluating the efficacy

of antiepileptic medications for CLBP, radicular, or neuro-pathic pain.

Observational studies

First generation antiepilepticsThe use of carbamazepine for CLBP or radicular symp-

toms has not been evaluated in clinical studies. Two casereports have documented efficacy for the treatment ofsciatica [37].

Second generation antiepilepticsNo formal clinical studies have demonstrated the effi-

cacy of gabapentin for CLBP.

Third generation antiepilepticsNo studies have been done specifically evaluating prega-

balin’s role in CLBP. One study was performed evaluatingthe efficacy of topiramate for CLBP [38]. The author’s cri-teria for inclusion were lumbar radiculopathy on clinicalpresentation and radiographic confirmation of a nerve rootcompression on magnetic resonance imaging or computedtomography/myelogram. They concluded that topiramateat a mean dose of 200 mg had a small but real analgesic ef-fect. This study is limited by a significant dropout rate(26%) because of intolerable side effects. Another studyevaluated topiramate’s role in treatment of CLBP [8]. Atdoses of 300 mg/d, topiramate was found to reduce painsymptoms and improve mood and quality of life. A small,open-label trial treating 14 patients found that at doses of400 mg/d, lamotrigine reduced pain in patients with intrac-table sciatica [39]. Other antiepileptics such as valproicacid, felbamate, and zonigran lack both FDA approvaland any meaningful clinical evidence supporting theirusage for treatment of CLBP or neuropathic pain.

Harms

TCAs

The main limitation of TCAs in the treatment of neuro-pathic pain conditions relates to side effects, which mayworsen as dosage increases (Table 3). Typical side effectsare usually anticholinergic in nature and include blurredvision, cognitive changes, dry mouth, constipation, andsexual dysfunction. TCAs should be used with caution inpatients with glaucoma, urinary retention, or autonomicneuropathy [40]. Orthostatic hypotension and cardiovascu-lar side effects (conduction defects, arrhythmias, tachycar-dia, stroke, myocardial infarction) are perhaps the mostconcerning side effects, and TCAs should be used with cau-tion in elderly patients or patients with known cardiac dis-ease [40]. Almost 20% of patients treated with nortriptyline(Pamelor, Aventyl) after a myocardial infarction may be atrisk for adverse cardiac events [41]. Occasionally, certainside effects may be considered potentially beneficial, suchas sedation for those patients who have poor sleep at night,appetite stimulation for patients with poor nutrition, orurinary retention for patients with urinary frequency.

In general, side effects are more common with the olderTCAs such as amitriptyline (Elavil, Clomipramine, Anafra-nil) and less common with the newer generation TCAs suchas nortriptyline and desipramine [40]. A comparison of nor-triptyline to amitriptyline in a PHN study demonstratedequivalent analgesia, but better tolerability with nortripty-line [42]. Side effects from amitriptyline may be significantenough that elderly patients may choose to accept painrather than continue to take the medication [43]. Minor ad-verse effects occur in 30% of patients taking TCAs,whereas 4% had major adverse effects. The number neededto harm for minor adverse reactions was 3.7 (2.9–5.2), andfor major adverse reactions the needed to harm was 22(13.5–58) [22].

SNRIs

Venlafaxine seems to be the least well-tolerated SNRI,combining serotonergic adverse effects (nausea, sexual dys-function, withdrawal problems) with a dose-dependent car-diovascular phenomenon (primarily hypertension), which isnot noted with duloxetine or milnacipran [44]. However, nodirect comparative data are available among the variousSNRIs. Side effects of duloxetine include nausea,

Table 3

Common side effects of tricyclic antidepressants

Medication Sedation Anticholinergic Hypotension Cardiac Seizures Weight gain

Amitriptyline þþþ þþþ þþþ þþþ þþ þþClomipramine þþ þþþ þþ þþþ þþþ þDesipramine 0/þ þ þ þþ þ þNortriptyline þ þ þ þþ þ þ

26 V. Chang et al. / The Spine Journal 8 (2008) 21–27

somnolence, hyperhidrosis, anorexia, vomiting, and consti-pation, with a higher incidence in the 60 mg twice dailydosage group; a higher side-effect related dropout ratewas noted in this group (12%) versus the 60 mg daily dos-age group (4%) [44]. Several studies have also noted ab-sence of cardiovascular changes related to duloxetine[2,31,32,35,45].

Antiepileptics

The clinical usefulness of carbamazepine is limited bysignificant side effects such as Steven-Johnson syndrome,agranulocytosis, aplastic anemia, and hepatic toxicity. Phe-nytoin is infrequently used for any pain states because ofadverse reactions and toxicity. Gabapentin side effects aredizziness (23.9%), somnolence (27.4%), peripheral edema(9.7%), ataxia (7.1%), and infection (8.0%) [9]. Pregabalinside effects are similar to gabapentin, including dizziness(23.8%), somnolence (11.7%), peripheral edema (11.7%),weight gain (12.8%), and vertigo (8.8%) [11].

One study attempted to evaluate topiramate’s role intreating CLBP and had a substantial dropout rate (26%) be-cause of intolerable side effects [38]. The most common ad-verse effects were paresthesias (38%), fatigue/weakness(34%), sedation (34%), and diarrhea (30%).

In a small, open-label trial treating 14 patients with la-motrigine 400 mg/d, the most common adverse effectsencountered were dizziness and diarrhea [13].

Summary

Although the evidence supporting the use of adjunctiveanalgesics for CLBP is limited, it appears reasonable touse low-dose TCAs in mild to moderately painful radicularsyndromes after acetaminophen and NSAIDs have beentried. In younger patients, our medication of choice is am-itriptyline; if side effects become lasting and intolerable,other TCAs are used such as nortriptyline may be used in-stead. If nighttime sedation is desired, trazadone (Desyrel)or the TCA, doxepin (Sinequan) are often used.

After those medications have been considered, antiepi-leptics such as gabapentin can also be used. This medica-tion requires titration of dosing with constant vigilancefor side effects. If the above fails, SNRI and newer gener-ation antiepileptics can be used. The expense and side-effect profiles of these brand name medications need to beweighed against possible efficacy in each individual pa-tient. For more severe pain, opioid analgesics can be used.If chosen appropriately, adjunctive analgesics can play animportant role in the treatment of spinal pain disorders.

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