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Pre sent-day knowledge about the chemical tr an smitters involved in pain and pain
modulation is immensely more advanced than onl y a few yea rs ago. This knowledge
extends into at least four different areas, the primary afferent system, the circu itry at
the level ofthe frrst synapse in the dorsal horn ofthe spinal cord, su praspina l sites of
pain modulation and fmally the descending control systems. The problem we address
ourselves is how thi s new knowledge can be applied to clinical pa in, to generate
diseasc models and to develop new tr eatment strategies.
Evidence has accumulated that substance P, a peptide with l1 am ino acids,
which in functional studies have been connected with pain. Whether substa nce P is a
'true' neurotran smitter or not is still under debate. It is known to excite neurones in
the spina l cord responding to nox iou s stim uli (Henry, 1976). The primary afferents
containing substance P form synaptic connections in areas of the spinal cord which
are rich in enkephalin fibres and opiate receptors (Hökfelt et al.. 1978; LaMotte, Pert
& Snyder, 1976). Opi ate receptors in the spinal cord seem to be highly significant for
the analgesic action of morphine. A few years ago , it was proposed that op iates act
pres ynaptically to inhibit the relea se of substa nce P (JeseIl & Iversen .1977). If
enkephalins are the naturalligands for the opiate receptors the y should have a
modulatory role via a simi lar mechanism. The opiate antagonist naloxone inhibits
the analgesic action also of enkephalin. If administered to a morphine na ive
individua l, howe ver, it will produce on ly very subtle effects a nd hardl y affect
experimental pain thresholds (Terenius, "1978). Gi ven to patient s in moderate
surgical pain, naloxone has a slight pain augmenting effect (Levine, Gordon, Jones &
Modulation of pain at supraspinal levels has recei ved much attention recentl y.
Several desc ending pathways, particularl y those emanating in areas which ar e rich in
serotonergic cell bodies (the raphe dorsalis and raphe magnus nucle i) ma y be
important (Fields & Basbaum, 1978; Besson , 1980). Therapeuticall y significant pain
relief can be obtained in man from stimulating periaqueductal brain areas which
ENDORPHINS A ND CENTRAL NEUROTRANSMITTERS IN CLIN ICAL PAIN 339
activate descending serotonergic systems (Hosobuchi, Adams & Linchitz, 1977). The
effect is naloxone-reversible, suggesting that one link is endorphin-mediated.
Despite all the new information, pain remains a large clin ical problem.
Particularly chronic pain, which by its mere existence represents a therapeutic
failure , needs more attention. With the recent increase in basic knowledge of pain
and pain modulation we have feit it to be timely to use neurochemical analysis as an
adjunct to neurologieal, psychological and psychiatrie evaluation of chronic pain
patients. We have also attempted to establ ish experimental paradigms which should
allow evaluation ofsensory processing and objective pain measures in such patients.
Clinical pain can be distinguished from experimental or triv ial pain by the fact that
the patient demands or receives treatment. Acute clinical pain has a sudden and
recent onset while chronic pain is of long duration or is marked by recurrent
episodes. Treatment of acute pain is well established pharmacologically while
treatment paradigms in chronic pain are frequentl y inadequate. The patient will go
into periods of despa ir and feelings of helple ssness. Chronic pain should therefore be
In very general terms, chronic pains can arise through two types of mechanisms;
either excessive, protracted stimulation of peripheral noc iceptors or, through
destruction of nervous tissue interfering with afferent input and leading to abnormal
CNS act ivity (Table I). Pharmacological treatment of chronic pain ar ising from
excessive stimulation of nociceptors such as cancer pain or arthritic pain, follows
methods established for acute pain. Depending on the severity, simple analgesics
(acet ylsalicylic acid and related congeners), non -narcotic centrally active analgesics
or narcotic analgesics may be given, with the strongest analge sics reserved for the
most severe pain syndromes and particularly for terminal illness. Contrarily, in pain
due to nerve damage , these drugs including the strongest ones, are usually not
particularly efficient or liked by the patients. Still most patients with this type of
chronic pain syndrome will üse simple analgesics notwithstanding their low
Table 1 Chronic pain, simple differentiationbasedon neuroanatomical considerations- some
I. Painfrom excessive stimulation 01 nociceptors
11. Pain originatingfrom lesions ofthe nervous system
A problem in the evaluation of treatment modalities in chronic pain is a lack of
suitable animal models. This is not only because animaI models are likely to reflect
all the psychic components of a clinical pa in syndrome but also because
conventional models for pain and testing of analgesics deal with pain elicited via
stimulation of peripheral nociceptors. As indicated in Table I, chronic pain
syndromes frequentl y arise as a result of destruction of nervous tissue. The need for
models ofthis kind ofpain has been realised only recentl y (Stemback, 1976). Surgical
interference of impulse flow in primary afferents or lesions at the spinal cord level in
Neurochemical studies of the pathogenesis of chronic pain
Previous studies of biochemical variables in chronic pain are sparse. Disturbed
adrenal func tion has been used as an index ofthe somatic involvement (as opposed to
psychogenic elements) with moderate success (Shenkin, 1964; Lascelles, Evans,
Merskey & Sabur, 1974). A more dire ct approach, involving neurochemical analysis
of cerebrospinal fluid (CSF) was introduced a few years aga (Terenius & Wahlströrn,
1975). Since CSF bathes the brain and spinal cord, its contents may reflect activity in
these structures. In most cases, lumbar CSF was obtained and the assay may therefore
reflect spinal processes particularly. However, it must be emphasized that this
approach is empirical and its relevance can only be assessed by establishing
correlations to c1inical variables. During the course of this work, there has been a
continuous increase in knowledge ofbasic mechanisms and various paradigms have
therefore been added to our investigations. The early studies were entirely devoted to
endorphins later anal ysis of monoamine metabolites was added and recently,
measurement ofsubstance P was introduced.
The original procedure (Terenius & Wahlström. 1975) was introduced at a time when
the chemical structure of endorphins was unknown. The procedure is based on a
receptor assay ; consequently it will measure receptor-active material and not inactive
metabolites. The activity in the assay will depend on concentration and affmity of
each contributing species. The chemical complexity of endorphins has later been
found to be very marked and active material in CSF is also chemically complex. T he
assay, as presently used, isolates two gross fractions with receptor activity, denoted
Fractions land II, respectively. More details on the assay have been described
elsewhere (Terenius & Wahlström, 1979). The Fraction I components seem to be
most relevant with regard to c1inical pain and its chemical characteristics have been
studied extensively. Several components exist, one of which seems related to
dynorphin (Wahlström & Terenius, 1980). The origin ofthe receptor-active material
is at least partly the spinal cord, as suggested from the prompt, segmentally related
increase in Fraction I endorphins on transcutaneous nerve stimulation (Sjölund,
The validity of using Fraction I measurements as an indicator of central
endorphinergic activity has been examined in various experimental paradigms.
Thus, a positive correlation exists between Fraction I levels and thresholds and
tolerance limits to experimentally induced pain (von Knorring, Almay, Johansson &
Terenius, 1978). A positive correlation also exists with regard to visually evoked
potentials (VEP) ; an individual who responded with an increased criterion with
increasing stimulus intensity had lower Fraction I levels than an individual who
showed no response (von Knorring, Almay, Johansson & Terenius, 1979). Arecent
study indicates that endorphin levels may predict our preparedness to tolerate
surgical pain. Aseries ofpatients, undergoing laparatomy gave CSF prior to surgery.
Following recovery, and within a few hours after surgery, the patients were allowed
to administer pethidine on demand via an intravenous catheter. The patients thus
titrated their pain level to an acceptable level. Pethidine steady-state levels could be
ENDORPHI NS AND CENTRAL NEUROT RAN SMITT ERS IN CLIN ICAL PAI N 341
established for plasma and CSF and it was found that there was a signi ficant inverse
correlation between CSF Fraction I levels and steady-state pethidine concentrations.
In other words, a patient with low preoperative endorphin levels would administer
more pethidine than one with high levels (Tamsen, Hartvig, Dahlström, Wahlström
Early studies on Fraction I levels in patients with chronic, mainly neurogenic pain,
showed the levels to be generally lower than in healthy volunteers. Another study,
where patients examined at a neurology clinic were the subjects, indicated that the
low level s were not a consequence of the pa in syndrome as such but rather of the
pathogenesis. Patients with neurogenic pain tended to ha ve low levels as previously
observed , but in patients where no somatic lesion was- evident, and the patient's
complaint s were less precise and appeared exaggerated, the levels were in the range of
healthy volunteers or higher (Table 2). More recent da ta suggest th at low endorphin
levels ma y be characteristic of po stlesional pain (neuralgia , causalgi a and so on )
where the lesion is within the nervou s system . Somatic pain, such as deri ving from
cancer or arthralgia , or pain better understood in psychi atric or psychological terms,
psychogenic pain, does not seem to be accom panied with low endorphin level s.
Contrarily, levels in psychogenic pain pat ients may be very high , as also observed in
patients with unipolar depression (Terenius, Wahlström & Agren, 1977), suggesting
that the pathogenesis of these syndromes may be similar. This assumption had been
proposed earlier on purely clinical grounds (Sternbach , 1974; von Knorring , 1975).
Table 2 Fraction 1endorphin levels in cerebrospinal fluid and the diagnosis of chronic pain.
(Almay et al.. 1979; Sjölund et al.. 1977; Terenius et al.. 1977).
Fraction I endorphin (pmol mt:' CSF)
Measurements 0/monoamine metabolites
Such measurements have a fairl y long history in psychi atric diagnosis and even if
interpretations are com plicated by several interfering variables, their clinical
potential is undisputed (cf. Goodwin , Muscettola, Gold & Wehr, 1978 ; Woods, 1980) .
A study ofmonoamine metabolite s in the CSF ofpatients with chronic pain revealed
particularly significant results for the 5-hydroxytryptamine (5HT) metabolite,
5-hydroxyindoleacetic acid (5HIAA). Levels of this metabolite were frequentl y low
as compared to normals and cases with low metabolite levels had significantly lower
Fraction I levels than those with higher levels (Alrnay, Johansson, von Knorring,
Sedvall & Terenius, 1980). In fact, it was found that the 5HIAA was similar to that
observed in endogenous depression, with approximately half ofthe cases having very
low levels . In depression, this sign ifies serious behavioural abnormality and strong
suicidal tendency ( Äsberg, Thoren, Träskman, Bertilsson & Ringberger, 1976).
Measurements of the dopamine metabolite, homovanillic ac id yielded less
So far our experience ofsubstance P measurements is fairl y limited. One unpublished
study illu strates its potential. Aseries of eight patients undergoing laparotomy and
allowed to administer pethidine postoperativelyon demand (see above) gave a CSF
sampie before surgery and one during optirnum use of pethidine. There was an
inverse relationship between postoperative substance P levels and pethidine
concentration (r=-o.82; P < 0.05). This fmding concurs with the model proposed
by Jessel & Iversen (1977), where opioids are assumed to act presynaptically to
inhibit substance P release . Studies are in progress to establish if there is a
relationship between substance P levels in CSF and the aetiology of various pain
Treatment strategies in chronic pain
The data presented in the previous section indicate that certain pain syndromes are
Moreover, opiates are anecdotally reported to be fairly inactive in neurogenic pain
syndromes. At present, there is no available pharmacological therapy which may act
particularly selective inhibitor of 5HT reuptake , zimelidine, was recently subjected
to a c1inical trial in chronic pain patients. A certain therapeutic efficacy was
established and what was particularly significant was the coincidence of therapeutic
and biochemical responses (Table 3). The tested population of chronic pain patients
was c1inically heterogenous and the neurochemical measurements underlined this .
The study also supports the case for diagnostic purposes. Incidentally, antidepressant
agents are frequently administered in psychogenic pain (Merskey & Hesler, 1972). It
is generally held that this treatment affects a 'psychic' reaction to pain. Our results
suggest that chronic pain and depression have a common neurochemical background
and that the therapeutic effects may be more specific.
Table 3 Changes in pain levels and concentrations of 5-hydroxyindoleacetic acid (5HIAA)
and Fraction I endorphin in CSF after treatment with zimelidine (2 x 25 mg, dail y) or placebo
for 4 weeks in chronic pain patients (Johansson & von Knorring, 1979; Joh ansson, von
Knorring, Sedvall & Terenius, 1980).
*P < 0.05 by analysis of covariance.
A very efficient treatment strategy for neurogenic pain is electrical or mechanical
(acupuncture) stimulation of peripheral sites in skeletal muscle. Stimulation
conditions may vary . Most frequently , electrical stimulation is delivered at high
frequency (WO-200Hz) but it mayaiso be used at lower frequency (I-2Hz) and then
be partly acting through acti vation of endorphin systems (cf. Table 4). A useful
feature of either treatment modality is a long duration of action; following a
stimulation session of 5-30 min , pain relief may last for 5-24 h. It remains an
important challenge to achieve a similar degree of pain relief with pharmacological
ENDORPHINS AND CENTRAL NEUROTRANSMITTERS IN CLINICAL PAIN 343
Table 4 Mechanism of stimulation produced analgesia using transcutaneous stimulation and
surface electrodes (Sjölund et al., 1977; Sjölund & Eriksson, 1979).
pharmacological targets may be the most efficacious, In this connection arecent
observation may be important since it suggests that potentiation ofthe SHT system
with reuptake inhibitors lowers the need for morphine or codeine (Ögren & Holm,
1980). Completely new categories ofpharmacological agents are also conceivable. An
antagonist to substance P should raise pain thresholds if this peptide indeed is
involved in pain transmission. If, as suggested above, neurogenic chronic pain
syndromes are connected with inadequate endorphin activity, drugs reinforcing these
systems, perhaps acting selectively at the level ofthe lesion would be useful. Another
consideration worth exploring is the condition ofreceptors involved in pain and pa in
modulation in patients with chronic pain. lt may be anticipated that continous
release of substance P or other substances transmitting nociceptivc information
would causc 'down-regulation' or desensitization of rcceptors; contrarily, patients
with damagc to nervous tissue may have supersensitive receptors and a usually
innocuous stimulus could produce pain. Presently, we do not know how to corrcct
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