Treatment of inflammatory, neuropathic and sympathetically maintained pain in a patient with Sjögren's syndrome

Purn,

so(19Y2) ?OS-10x

~(‘8lY92 Elsevier

Science Publishers

B.V.

All rights reserved 0304.39SY/92/$05.00

PAIN 021 In

Treatment

of inflammatory, neuropathic and sympathetically maintained pain in a patient with Sjijgren’s syndrome

Bradley

S. Galer

“, Michael

C. Rowbotham and Howard

“vb,Kurt Von L. Fields

Miller

‘, Anne

Walton

”

h’~rrrtt?lcvfl.s of‘ ” hkurdo~~~ utld ” Anrsthesiu, School of Medrcinr, Unirwsity of Culrfim~w ut Sun Frunctsco. Surt Frunci.sco. C‘A 94143 (IJSA) (Received

I3 December

1991. revision received

I3 March

IYYZ. accepted

I5 March

lYY2)

We present a case of Sjogren’s syndrome with a painful peripheral neuropathy where pain control Summary required both anti-inflammatory and sympatholytic treatments. This case suggests that the pain in some inflammatory disorders with nerve injury may have a component mediated by an alpha adrenergic receptor. Key words:

Sjiigren’s

syndrome;

Sympathetically

maintained

Introduction Sjogren’s syndrome (SS), an auto-immune inflammatory disease, is defined as the simultaneous presence of keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth) in the absence of another chronic inflammatory connective tissue disease (Bjerrum and Prause 1990). Lymphocytic and plasmocytic infiltration destroys exocrine glands, resulting in the characteristic dry eyes and mouth. Arthralgias, usually in the finger joints, and myalgias occur in up to 88% of patient’s with SS (Bjerrrum and Prause 1990). Peripheral nervous system abnormalities, typically sensorimotor or pure sensory neuropathy, are present in lo-32c% of SS patients (Alexander et al. 1982; Mellgren et al. 1989) and may occur prior to glandular involvement (Kaplan et al. 1990). Painful paresthesias are common in both types of neuropathies (Griffin et al. 1990; Kaplan et al. 1990, 1991; Mellgren et al. 19891, suggesting that, in addition to pain that may directly result from the inflammatory process, some SS patients may suffer from pain of neuropathic origin. We describe a woman with primary SS and an associated peripheral neuropathy, whose pain descriptions, physical examination and response to various

pain;

Neuropathic

pain;

Case presentation A 3h-year-old 1984 when

attorney

she became

which she was treated treatment hands.

was in excellent

ill with a fever. with penicillin.

was completed,

face and feet.

USA.

Bradley

S. Galer,

of Washington,

M.D.,

RC-95,

Multidisciplinary Seattle,

WA

98145.

until

December

and otitis for

a non-painful

and laryngospasm

and methylprednisolone.

edema of her required

During

treat-

the ensuing

month, the joints of her hands. feet and knees became painful, red. swollen and tender. antibody

Erythrocyte

and rheumatoid

By April mouth

and

a worsening

of

was complaining her

burning pain and hypersensitivity clearly which

distinct

from

her joint

was most pronounced

biopsy was diagnostic From October oral steroid prednisonc

sedimentation

arthritic

of dry eyes and dry

pain.

She

also noticed

of the skin of both hands and feet, pains,

and numbness

in her finger

tips.

A

in her hands. 5alivat-y gland

for Sjogren’s syndrome.

19x5 to February

pulse therapy. (20 mg/day)

19X7 the patient was treated with

NSAIDs,

hydroxychloroquine,

with partial

pain relief.

and daily

A trial of auranofin

(oral gold) was not tolerated.

Her medical

condition

February

intravenous

methylprednisolone

lYX7 and high-dose (I000

mg, 3 times/month)

excellent

worsening regimen

was

initiated,

deteriorated which

(12.5 my/week)

at first

ued to have significant

pain and disahility.

pains.

was begun due to a

physical disability.

a gradual and moderate

in

pulse

pain relief of both her joint and cutaneous

of pain and increasing

produced

stiff.

rate. antinuclear

factor were all normal.

19x5, the patient

In late 19XX oral methotrexate University

health

phatyngitis,

Two days after the penicillin

she developed

Wheezing

ment with epinephrine

therapy

C’orrz~pondencc, to:

infusion

therapeutic interventions strongly suggest that in addition to inflammatory pain there is a pain component that is both neuropathic and sympathetically maintained.

produced

Pain Center.

Phentolamine

Although

improvement.

this

she contin-

206 When

first seen at the UCSF

IYYO, she complained

of two

burning and hypersensitivity pain, tenderness was being day),

with

methotrexate

Her

langeal

joints

present.

were tender,

Cranial

nerve

testing.

Distal

cotton

wisp was present.

marked allodynia pain.

On examination, but no redness,

These

swelling

was normal, sensory

pinprick

infucushln-

or deformity

was

as was motor

and and

loss to pinprick. elicited

She

metatarsopha-

same areas of sensory

and repetitive

No abno~ality

intravenous and

and

(200 mg/

she was mildly

metacarpophalangeal

symmetrical

and feet

sulindac

and a monthly

examination

reflex

m &~4

a symmetrical

of her hands and &I.

(12 mg/day),

(20 mg/week)

in appearance.

Practice

problems:

in the joints

prednisone

sion of 500 mg solumedrol. goid

Faculty

pain

of the skin of her hands

and stiffness

treated

Neurology

severe

cold

loss

severe

in direction sense was detected.

studies

with

revealed

mild inflammation. no other

etiology

Extensive

serologic

for her disorder

underwent

a left stellate

ganglion

block

she became

orthostatic.

better

f3y the fourth lor

pain rchcf

phentolamlnr

pain

(mean.

first

from

1%~

time

in

IO meters

to

VAS

minimum,

following

each

pain relief hcgin.\

scorch

infusion,

tntu~ticm.

I’h~nl,~yhenl;lmlll~.

10 rng

hypot~~u\icu~.

tntu>ion.

11 \\cch\

\cvcraI

I

At

years.

attcr

Ijr
ihr

the

tirsr

\\alkln.ti

to LXI

toler.~n~~c

.‘I phcntolamrnc

arc prescntcd

a plateau

-7 wcrk.k

I ICI

kilomelcr.

for

.I study

of approxlmatrly

po\t-infuGon.

mtuslon\

111FIN. I. III the d+

IIOIC~

she consistently

reache>

Immediately

before

1YOl. a detailed

following before

changes the

her feet

the deficits were

the lack of cold sensation

the

Incrc;tsc ;II

YO’;

pawn thou

111

I uczk

gr,ldu,lll!

InfusIon

the allodynia touch

improved. evident

her palms

pa\t

IX months.

evc~) .1 weeks.

to each

that was prcxrnt

and pmprick

in her legs &lore

and

the Infusion

had

pinprick

and cahes. the

She notes

puticnt not

has had only

the patient

,i phcntolaminc

a plogressivc

of phentolamine

notices

region.

recurrence

improvcInfuGonx.

Several

of Joint

She is now ahlc

to do daily

capacity

for ‘revera/ hours without

hou\chold

tor a non-profit

da)\

ot fatigue.

of her palms and soles of her feet and a minor

in II managerial

111

dcpresscd:

blight burning pain.

111hc!

scnsaiil)n

in the arca> of marked

in the size of Ihe painful

infusion

in

and the

and dccreitsed

hut still slightly

of a11 her pains since the initiation

but also a reduction

ml’uamn

wa\ performed

w;,h ahscnl

in light

within

the

a phentolamlne

examination

No change was ohsewed

summation For

I h after

in her palms

and fingers

normalized.

and

sensory

were documented:

infusion

ICL.I and catvcs:

prior

phcnrolamlnc

,I> 111~ tl~r\c H;I\ InL.r<..1\
wltht)u[

and maximum)

that

11.1(1

,~nd .IH

to rcturnb.

August

walk

chores.

organization.

a

dcgrcc work arid

pain or fatigue.

-7

90

Discussion

80

The triad of arthritis, keratoconjunctivitis sicca and xerostomia in a middle-aged woman is characteristic ot SS. The diagnosis is best confirmed by salivary gland biopsy. Common extraglandular manifestations of SS include fatigue, myalgias, diarrhea, numbness and pain (Bjerrum and Prause 1990). Our patient had all of the aforementioned signs and symptoms of SS and a confirmatory biopsy. Of interest in this patient is lwr response to various therapies aimed at modulating a possible sympathetic nervous system component of her pain. Two distinct pains were described by the patient: disabling joint pain and tenderness and distal symmetrical cutaneous burning and sensitivity. On physical examination, the patient’s joints of her hands and feet were tender but not red, swollen or deformed. Kadiological studies of the hands failed to reveal joint changes or osteopenia. A distal symmetrical sensory polyncuropathv was present on neurological examination.

70 60 s -E ff

the

lncrcased

mcnt

I;IILI

\c’x~ able lo wear her wseddinp ring and MC hci finger5

part-lime

700

the third

to 40 mg daily, produced

3 v.cch\

pat11 r,~t~ng 01 I:

of 5 mm and 5 ,‘I) on Ihc pail1 ICIICI \c.,I~c

for 3 weeks. After

daily.

po+infu\ron.

in April 1YW with 10 ml of 0.25% bupivacaine which, on a loo-mm VAS Pain Rating scale, reduced her pain from 65 mm to 30 mm and resulted in a Horner’s syndrome and warming of her left arm. For 24 h the burning pain in her left hand was decreased by approximately 40%. with the other extremities unaffected. In May IYYO,an intravenous lidocaine infusion was performed (323 mg over 60 min), which reduced her pain from 51 mm to 18 mm on the VAS, with pronounced improvement of the cutaneous pain and hyperalgesia for 4 h. Because of this significant pain relief in response to the intravenous lidocaine, oral mexiletine treatment was initiated. However, the patient only briefly tolerated a daily dose of 600 mg, which produced only modest pain relief. Two weeks following the lidocaine infusion an intravenous infusion of phentolamine was performed (35 mg over 60 min). This infusion markedly reduced both the superficial burning pain and the The patient

rating

VAS

wah initiatctl.

ftmd

of vasculitis.

1r11u~or1 pcrtolmL,cl

a prs-inlu\iorl

treatment

~~rnbulati~~n

and radiologic

lasted

oral guanethidinc

pnttrnt

and no evidence

with

VAS

end-infusIon

displayed

and antaigic. The amplitude of the sural nerve sensory action potential was reduced on the left. Biopsy of this nerve revealed diffuse edema,

phentolammc

result\.

Pain relief

l~)ng-Iasting

was slow

consistent

X\ repeat similar

50 40 30 20 10

-_

~ O-l,

I

Pre-infusion

1

1 hour post-infusion

Fig. 1. Change in pain VAS during the first 5 phentolamine (mean. minimum and rn~rnurn}.

infusions

Besides the inflammatory component to her joint pain. the distribution and quality of her cutaneous pain support additional neuropathic and sympathetic components, as does the response to various therapeutic interventions. Both neuropathic and sympathetically maintained pain may respond to intravenous lidocaine infusion (Edwards et al. 19535; Kastrup et al. 1987; ~~~wb~)tham et al. 1991). In cxper~mentally damaged peripheral nerves, intravenous lidocaine has been shown to inhibit abnormal spontaneous and evoked activity in A-delta and C fibers at doses much lower than required to block normal axonal conduction (Chabal et al. 1989; Maclver and Tanelian 1990; Tanelian and Maclver 1991). Involvement of the sympathetic nervous system in this patient’s pain syndrome is strongly suggested by pain relief obtained from several therapies aimed at selectively reducing sympathetic tone. Stellate ganglion blockade, intravenous phentolamine, and oral guanethidine and phcnoxybenzamine all have produced significant pain relief. Alpha-adrenergic blockade with intravenous phentolamine has been advocated as a sensitive diagnostic test for sympathetically maintained pain (Raja et al. lY91). Interestingly, both the joint and cutaneous pains were significantly alleviated by the addition of a daily oral sympatholytic agent and intravenous phentolamine infusion every 3 weeks to the maintenance anti-inflammatory regimen. In addition, the improvement on sensory examination following a phcnt~)lamine infusion, specifically the loss of allodynia. the n~~rmaiizati~~nof cold sensation and a better sense of light touch and pinprick, may signify a dysfunctional, yet potentially reversible, link between the peripheral and sympathetic nervous systems. Similiar changes were documented in patients with sympathetically maintained pain following regional guanethidine block. with normalization of both thermal and vibratory pain thresholds (Wahren et al. 1991). A contribution of the sympathetic nervous system to inflammatory pain has recently been suggested. It has been demonstrated that postganglionic sympathetic neuron can itself release pro-in~ammat(~~ prostaglandins (Gonzales et al. 1991: Levine et al. 1988). In humans, regional intravenous guanethidine in patients with longstanding rheumatoid arthritis (RA) produced a significant decrease in pain compared to placebo (Levine et al. 1986). Conversely, in patients with reflex sympathetic dystrophy, marked inflammation and pain of the synovial joints is present, which may respond to glucocorticoids (Kozin et al. 1976), guanethidine (Bonica 1979) and other sympatholytic agents (Bcnzon et al. 19X0). In addition to a direct contribution of sympathetic post-~~inglionics and primary afferents to inflammato~ pain, animal models of neuropathic pain have revealed that electrical stimulation of sympathetic efferents acti-

vates primary afferent terminals in experimental neuromas through alpha-adrenergic transmission (Devor and J&rig 1981). Recently, it has been shown that experimental partial nerve injury induces increased responsiveness of C-fiber nociceptors to norepinephrine and sympathetic stimulation which is mediated by alpha2-adrenergic receptors (Sate and Per1 19911. In addition, experimentai painful peripheral neurop~ithy in rats was shown to be alleviated by symp~~thetic blockade (Shir and Seltzer 1991). Similarly, there is clinical evidence in man that sympathetically maintained pain may involve a peripheral alpha-adrenergic mechanism (Treede et al. 1991). Hence, both animal and human studies support a direct link between damage to the peripheral nervous system and catecholamine sensitivity in the development of pain. In summary, both anti-inflammatory and sympatholytic treatments were required to maintain adcquatc pain control in this patient with diagnostically proven SS and an associated sensory neuropathy. This cast suggests that in some in~ammato~ disorders both nerve damage and the activity of the sympathetic ncrvous system are relevant to the etiology of the pain. This multifactorial mechanism of pain raises the possibility of alternative strategies for improving the therapy in these patients.

Acknowledgement The authors would like to thank Dr. Jon D. Levine for his critical review of the manuscript. This work was supported by N.I.H. Pain Research Training Grant NSO7265. References Alexander.

E.L..

Neurologic Medicine, Benzon.

Provost, T.T.,

Stevens. MB.

and Alexander.

of

Sjiigren‘s

complications hl (1982)

H.T.,

GE.

syndrome.

247-257.

Chomka,

sympathetic

primary

CM.

and Bruner.

EA..

Treatment

dystrophy with regional guanethidine.

of reflex

Ane\th.

Analg!..

59 t 1980) 5tX&-502. Bjerrum. tive

K.

and Prause,J.U., PrimarySjiigren‘s

cl~scription

of the

disease,

7 > ‘X.+%X. Bon&. J.J.. C‘ausalgiaand other J.J. Bonica.

J.C.

Lieheskind

vances in Pain Research

Clin.

C.,

Russell,

venous lidocaine.

and Therapy.

tive fibers

L.C.

and Burchiel.

tocainide

originating

Rileurn., 8 (lYY1)r

reflex sympathetic and D.

Vol.

(Eds.1.

In: Ad-

3. Proc. 2nd World 1970. pp. 141-Iho.

K.J..

and mexiletine

in rat sciatic

dystrophicy.

Albe-Fcssard

Congress on Pain, Raven Press, New York. Chahal.

syndrome: a subjec-

Exp.

The

effect

of tntra-

on spontaneously

neuromac.

Pain.

3X

ac-

( 19XY)

3.33-33x. Devor.

M. and JEnig, W., Activation

in a neuroma

by stimulation

of myelinated

of the sympathetic

Neurosci. Lett., 24 (1981)43-47. Edwards.W.T.. Habib, F., Burney. R.G. lidocaine

in the management

review of 211 cases, Regional

ending

and Begin. G.. intravenous

of various Anesth..

afferents

supply in the rat.

ltl

chronic

pain states: a

(lW.5) 1--CL

208 Gonzales, R., Sherbourne, C.D., Goldyne, ME. and Levine, J.D.. Noradrenaline-induced prostaglandin production by sympathetic postganglionic neurons is mediated by alpha,-adrenergic receptors, J. Neurochem., 57 (1991) 1145-l 150. Griffin, J.W., Cornblath, D.R., Alexander. E., Campbell, J., Low, P.A., Bird, S. and Feldman, E.L., Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjiigren’s syndrome, Ann. Neurol., 27 (1990) 304-315. Kaplan, J.G., Rosenberg, R., Reinitz, E., Buchbinder, S. and Schaumburg. H.H., Peripheral neuropathy in Sjiigren’s syndrome. Muscle Nerve, 13 (1990) 570-579. Kaplan, J.G. and Schaumburg, H.H., Predominantly unilateral neuronopathy in Sjogren’s syndrome, Neurology. 41 (1991) 948949. Kastrup, J., Petersen, P., Dejgard, A., Angelo, H.R. and Hilstead, J., Intravenous lidocaine infusion - a new treatment of chronic painful diabetic neuropathy?, Pain. 28 (1987) 69-75. Kozin, F.. McCarty, D.J., Sims, J. and Genant. H., The reflex sympathetic dystrophy syndrome. 1. Clinical and histological studies: evidence for bilaterality, response to corticosteroids and articular involvement, Am. J. Med., 60 (1976) 321-33 I. Levine, J.D., Fye, K., Heller, P., Basbaum. Al. and Whiting-O’Keefe. Q., Clinical response to regional intravenous guanethidine in patients with rheumatoid arthritis, J. Rheumatol.. 13 (1986) 1040-1043. Levine, J.D., Coderre, T.J. and Basbaum, Al.. The peripheral nervous system and the inflammatory process. In: R. Dubner, G.F. Gebhart and M.R. Bond (Eds.), Pain Research and Clinical Management, Vol. 3, Proc. Vth World Congress on Pain. Elsevier, Amsterdam, 1988, pp. 33-43. Maciver, M.B. and Tanelian, D.L., Lidocaine blocks A-delta and C

fiber injury discharge without altering uc’ryc conduction. SC,; Neurosci. Abst., 16 (1990) h3h. Mellgren, S.I., Conn, D.L.. Stevens, J.C. and Dyck. P.J.. Peripheral neuropathy in primary Sjogren‘s syndrome. Neurology. 39 (19X9) 390-394. Raja, S.N., Treede, R.D.. Davis, K.D. and (;tmpbell. J.N.. Systemic alpha-adrenergic blockade vvith phentolamine: a diagnostic teat for sympathetically maintained pain, Anesthesiology. 73 ( 1991) 691-698. Rowbotham, M.C., Reisner-Keller. L.A. and Fields. H.L.. Both iiftravenous lidocaine and morphine reduce the pain of posthcrpetit neuralgia, Neurology, 41 (1991) 1024--102X. Sato, J. and Perl. E.R., Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science, 251 (1991)

1608-1610. Shir. Y. and Seltzer, Z., Effects of sympathectomy in a model of causalgiform pain produced by partial sciatic nerve injury in rats. Pain, 45 (1991) 309-320. Tanelian. D.L. and MacIver, M.B., Analgesic concentrations of lidoCaine suppress tonic A-delta and C fiber discharges produced by acute injury, Anesthiology, 74 (1991) 9344936. Treede, R.D., Raja, S.N., Davis. K.D.. Meyer, R.A. and Campbell, J.N., Evidence that peripheral alpha-adrenergic receptors mediate sympathetically maintained pain. In: M.R. Bond, J.E. Charlton and C.J. Woolf (Eds.), Pain Research and Clinical Management. Vol. 4, Proc. VIth World Congress on Pain, Elsevier. Amsterdam, 1991, pp. 377-382. Wahren. L.K., Torebjork. E. and Nystrom, B.. Quantitative sensorS; testing before and after regional guanethidine block in patients with neuralgia in the hand, Pain, 46 (1991) 23-30.