116
PAIN 01’144
Genuine resistance to opioids -
fact or fiction?
Staffan Am& ” and Bjiirn A. Meyerson ’
(Received 5 March lY91, accepted 26 June 1901)
Dear Editor, In Pain, 43 (1990) 273-286 Dr. Portenoy et al. have presented a paper on ‘The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid research.’ In your editorial in the same issue of Pain you point out that ‘Am& and Meyerson are the authors of one of the papers most heavily criticized by Portenoy et al. for suggesting that neuropathic pain does not respond to opioids.’ Our paper was titled ‘Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain’ 11, see also 2, 3, 61. We found insensitivity to opioids administered double-blind with a strict protocol to some chronic neuropathic and idiopathic pain disorders using i.v. opioids in doses effective in chronic nociceptive pain conditions which were included as a control group in our study. Although the title of our paper had a somewhat provocative phrasing, it should be perfectly clear that nowhere in the text did we maintain that the issue of responsiveness of neuropathic pain to opioids is finally settled, nor did we suggest that any ‘patient in pain should be deprived of open trial’ of the analgetic efficacy of narcotics (cf., editorial). On the contrary, this is part of our daily clinical practice when dealing with all cancer-related pain and it also applies to a number of other forms of pain. The essence of the message of our publication was to emphasize the need of further, well controlled studies of opioid responsiveness with particular regard to the pathophysiolo~ of different pain mechanisms. We agree with Portenoy et al. that there is a compelling need for scientific rigour in the study of opioid respon-
Correspondence to: B.A. Meyerson, Dept. of Neurosurgery. Karolinska Stukhuset, P.O. Box 60500. S-10401 Stockholm, Sweden.
siveness. They have enthusiastically argued in favour of one of several possible methods - or paradigms - to approach this important issue. They propose that responsiveness to opioids is a continuum which applies to all forms of pain regardless of the underlying mechanisms. The endpoint of this continuum is defined as analgesia (not partial but complete) or intolerable side effects. To our view these two endpoints are fundamentally different and cannot be used interchan~ably when discussing this problem. In principle, the presence of side effects is not relevant for the issue if truly opioid resistant forms of pain do in fact exist. The underlying mechanism of responsiveness is of course the existence of sufficient amounts of opioid receptors, or subgroups of receptors, the complete occupancy of which will result in a complete blocking of that particular form of pain. If that is the case the efficacy is just a question of dosage although in the test situation this may be difficult to achieve due to side effects. However, most experienced clinicians have seen opioid native patients who are capable of differentiating analgesia from sedation also when tested with exceptionally high doses of systemic opioids. Many of these patients still claim that their original pain is largely unaffected though it does not bother them as much. The other endpoint of a continuum of responsiveness proposed by Portenoy et al. is unmanageable side effects. This concept just relates to the clinical usefulness of opioid analgesics and does not tell anything about responsiveness per se. Thus, analgesia and side effects cannot be used as alternative endpoints in assessing whether a certain form of pain is responsive or resistant to an analgesic. Portenoy et al. point to a number of patient-related and time-related factors which must be taken into account. Although trivial, these factors are relevant to all forms of assessment of treatment, not only pharmacological, and when used in order to support the view
117
that virtually all forms of pain are susceptible to opioids, some of them are interpreted in a rather biased way. For example, when discussing ‘breakthrough’ pains it is claimed that the well known, failing effect of opioids is due to the drug not being administered fast enough. It is indeed a common experience, for example, that movement of pathological fractures produce a pain which is rarely possible to counteract by opioids. The same applies to shooting and lancinating pain components in neuropathic conditions. One obvious message of the paper of Portenoy et al. is that there is little evidence supporting the resistance of neuropathic pain in general to opioids, but their interpretation of available data is indeed biased. They question all previous reports, whether anecdotal or systematically controlled, which indicate that such forms of pain may be resistent. Conversely, they fail to admit that there is actually no systematic, controlled study demonstrating that such pain does respond to opioids. Their own data, presented in the paper and referred to in other reports, are not convincing and do not contribute to the resolution of the issue of opioid responsiveness [cf., 81. They report 28 cases of ‘mixed’ neuropathic syndromes in cancer patients and in 4 patients with ‘pure’ neuropathic pain. No information is provided about how the test was performed, the dosage used and side effects with regard to sedation. They have chosen to define significant pain relief as more than 50% reduction of VAS values. This does not tell anything about the quality of analgesia, nor about the possibility to reach the endpoint of complete pain suppression by escalation of doses. The authors also report in more detail a patient with syringomyelia and pain of moderate intensity, 39 on a 100 mm VAS. They assessed concomitantly pain reduction and sedation, but it is not told how the latter variable was measured and how the patient was instructed. The graph illustrating the case shows that almost 40% of the pain reduction occurred already immediately after the start of the infusion before there was any significant drug level in the plasma, and 80% of the pain relief is noted already at a time when there was only a moderate plasma concentration of the drug. This level of analgesia was achieved with a remarkably low dose (3 mg/h hydromorphone which is equipotent to approximately 15 mg morphine). In fact, this dosage is equal to that which the authors in their discussion repeatedly and somewhat arrogantly refer to as ‘usually effective’ (cited from our paper on the same subject). It is apparent that this particular patient is an exceptional case which does not justify the generalized conclusion than neuropathic pain is responsive to opioids in a dose-dependent fashion. We have never been able to reproduce such an effect in a patient with a similar type of pain. For example, a recent opioid naive patient with central pain of supraspinal origin, rated as 70 on VAS, was subjected
to 70 mg morphine i.v. infused over 45 min. She still reported the same pain level and then went into a state of confusion which had to be reversed with naloxone. It should be added that the paradigm employed and recommended by Portenoy et al. has been used by others [e.g., 7, 93 including ourselves as described in a recent publication [4]. In general the outcome of such tests, which usually also have included placebo injections, has been that neuropathic pain generally does not respond to opioids if care is taken to account for the sedative effects. The same conclusion has been reached in a recent study which used a methodology similar to our original study [Kupers and Gybels, personal communication]. It should be emphasized that in our paper we have never argued that all forms of neuropathic pain in all patients with such pain are unresponsive to opioids. In a ‘Letter to the Editor’ [31 we proposed that neuropathic pain trigged by nociceptive events may be sensitive to opioids and we also discussed the possible responsiveness of so called ‘nerve trunk pain,’ recently reviewed by Asbury and Fields [5, see also 101. In some patients it appears as if there are components of a neuropathic pain condition which may be sensitive to opioids and it might well be that this portion of their pain represents a nerve trunk pain component. It is reasonable to assume that intact nociceptive nerve fibres, in a peripheral nerve or a root, subjected to local pressure will fire in a relatively normal fashion, similar to that in response to a peripheral noxious stimulus; this type of activation would be perfectly well controlled by opioids. However, in the case of a permanent damage or dysfunction (with hyperpathia) of peripheral or central nervous structures, the perception of pain may be generated by different and aberrant mechanisms. All evidence available to date from anecdotal reports and systematic controlled studies indicates that such pain unfortunately appears to be unresponsive to opioids. Most of the issues which ought to be further explored and which were presented in the paper by Portenoy et al. were in fact discussed in our article, e.g., differential responsiveness to different opioids, subgroups of receptors, importance of dosage with relation to individual sensitivity, etc. We fully agree that opioids should never be withheld from any patient with severe pain. Also a lack of response with moderate or heavy doses should not stop further trials with even higher doses. However, this philosophy in combating pain should never lead us to disregard scientific data even though such knowledge ‘would contribute to the bias against opioids.’ Instead, our common goal should be to discover for which pain conditions opioids are effective and when they are not to find new remedies, pharmacological or others, for pain which appears to be inherently unresponsive to opioids.
5 Ashury.
Keferences
A.K.
damage: I ArnCr. S. and Meyerxon. on ncuropathic
B.A.. Lack of analgesic effect of opioids
and idiopathic
forms of pain.
Pain.
23 (IWXI
Al-nb.
S. and Meycrson.
B.A..
Reply
‘(‘iin opiates relieve neuropathic 3 A&r.
S. and Meyerson.
B.A..
to Howard
L.. Fields
on
pain’?‘, Pain. 35 (1488) 366 -367. Reply to Dr. Vecht‘\
comments.
il.l...
S.. Bertlcr.
Management
K..
Boluntl.
C.
of Pain in the Terminal
dations from the Swedish National i\llmiinn:i
Fiirlaget.
lorthes
Stockholm.
and
Meyerson.
Stage of Life.
Board of Health
19x4. pp. 47.
B.A..
The
Recommenand Welfare.
Can Y..
and
Overview. X Stcrnbach,
PAIN 01’144
Genuine resistance to opioids -
fact or fiction?
Staffan Am& ” and Bjiirn A. Meyerson ’
(Received 5 March lY91, accepted 26 June 1901)
Dear Editor, In Pain, 43 (1990) 273-286 Dr. Portenoy et al. have presented a paper on ‘The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid research.’ In your editorial in the same issue of Pain you point out that ‘Am& and Meyerson are the authors of one of the papers most heavily criticized by Portenoy et al. for suggesting that neuropathic pain does not respond to opioids.’ Our paper was titled ‘Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain’ 11, see also 2, 3, 61. We found insensitivity to opioids administered double-blind with a strict protocol to some chronic neuropathic and idiopathic pain disorders using i.v. opioids in doses effective in chronic nociceptive pain conditions which were included as a control group in our study. Although the title of our paper had a somewhat provocative phrasing, it should be perfectly clear that nowhere in the text did we maintain that the issue of responsiveness of neuropathic pain to opioids is finally settled, nor did we suggest that any ‘patient in pain should be deprived of open trial’ of the analgetic efficacy of narcotics (cf., editorial). On the contrary, this is part of our daily clinical practice when dealing with all cancer-related pain and it also applies to a number of other forms of pain. The essence of the message of our publication was to emphasize the need of further, well controlled studies of opioid responsiveness with particular regard to the pathophysiolo~ of different pain mechanisms. We agree with Portenoy et al. that there is a compelling need for scientific rigour in the study of opioid respon-
Correspondence to: B.A. Meyerson, Dept. of Neurosurgery. Karolinska Stukhuset, P.O. Box 60500. S-10401 Stockholm, Sweden.
siveness. They have enthusiastically argued in favour of one of several possible methods - or paradigms - to approach this important issue. They propose that responsiveness to opioids is a continuum which applies to all forms of pain regardless of the underlying mechanisms. The endpoint of this continuum is defined as analgesia (not partial but complete) or intolerable side effects. To our view these two endpoints are fundamentally different and cannot be used interchan~ably when discussing this problem. In principle, the presence of side effects is not relevant for the issue if truly opioid resistant forms of pain do in fact exist. The underlying mechanism of responsiveness is of course the existence of sufficient amounts of opioid receptors, or subgroups of receptors, the complete occupancy of which will result in a complete blocking of that particular form of pain. If that is the case the efficacy is just a question of dosage although in the test situation this may be difficult to achieve due to side effects. However, most experienced clinicians have seen opioid native patients who are capable of differentiating analgesia from sedation also when tested with exceptionally high doses of systemic opioids. Many of these patients still claim that their original pain is largely unaffected though it does not bother them as much. The other endpoint of a continuum of responsiveness proposed by Portenoy et al. is unmanageable side effects. This concept just relates to the clinical usefulness of opioid analgesics and does not tell anything about responsiveness per se. Thus, analgesia and side effects cannot be used as alternative endpoints in assessing whether a certain form of pain is responsive or resistant to an analgesic. Portenoy et al. point to a number of patient-related and time-related factors which must be taken into account. Although trivial, these factors are relevant to all forms of assessment of treatment, not only pharmacological, and when used in order to support the view
117
that virtually all forms of pain are susceptible to opioids, some of them are interpreted in a rather biased way. For example, when discussing ‘breakthrough’ pains it is claimed that the well known, failing effect of opioids is due to the drug not being administered fast enough. It is indeed a common experience, for example, that movement of pathological fractures produce a pain which is rarely possible to counteract by opioids. The same applies to shooting and lancinating pain components in neuropathic conditions. One obvious message of the paper of Portenoy et al. is that there is little evidence supporting the resistance of neuropathic pain in general to opioids, but their interpretation of available data is indeed biased. They question all previous reports, whether anecdotal or systematically controlled, which indicate that such forms of pain may be resistent. Conversely, they fail to admit that there is actually no systematic, controlled study demonstrating that such pain does respond to opioids. Their own data, presented in the paper and referred to in other reports, are not convincing and do not contribute to the resolution of the issue of opioid responsiveness [cf., 81. They report 28 cases of ‘mixed’ neuropathic syndromes in cancer patients and in 4 patients with ‘pure’ neuropathic pain. No information is provided about how the test was performed, the dosage used and side effects with regard to sedation. They have chosen to define significant pain relief as more than 50% reduction of VAS values. This does not tell anything about the quality of analgesia, nor about the possibility to reach the endpoint of complete pain suppression by escalation of doses. The authors also report in more detail a patient with syringomyelia and pain of moderate intensity, 39 on a 100 mm VAS. They assessed concomitantly pain reduction and sedation, but it is not told how the latter variable was measured and how the patient was instructed. The graph illustrating the case shows that almost 40% of the pain reduction occurred already immediately after the start of the infusion before there was any significant drug level in the plasma, and 80% of the pain relief is noted already at a time when there was only a moderate plasma concentration of the drug. This level of analgesia was achieved with a remarkably low dose (3 mg/h hydromorphone which is equipotent to approximately 15 mg morphine). In fact, this dosage is equal to that which the authors in their discussion repeatedly and somewhat arrogantly refer to as ‘usually effective’ (cited from our paper on the same subject). It is apparent that this particular patient is an exceptional case which does not justify the generalized conclusion than neuropathic pain is responsive to opioids in a dose-dependent fashion. We have never been able to reproduce such an effect in a patient with a similar type of pain. For example, a recent opioid naive patient with central pain of supraspinal origin, rated as 70 on VAS, was subjected
to 70 mg morphine i.v. infused over 45 min. She still reported the same pain level and then went into a state of confusion which had to be reversed with naloxone. It should be added that the paradigm employed and recommended by Portenoy et al. has been used by others [e.g., 7, 93 including ourselves as described in a recent publication [4]. In general the outcome of such tests, which usually also have included placebo injections, has been that neuropathic pain generally does not respond to opioids if care is taken to account for the sedative effects. The same conclusion has been reached in a recent study which used a methodology similar to our original study [Kupers and Gybels, personal communication]. It should be emphasized that in our paper we have never argued that all forms of neuropathic pain in all patients with such pain are unresponsive to opioids. In a ‘Letter to the Editor’ [31 we proposed that neuropathic pain trigged by nociceptive events may be sensitive to opioids and we also discussed the possible responsiveness of so called ‘nerve trunk pain,’ recently reviewed by Asbury and Fields [5, see also 101. In some patients it appears as if there are components of a neuropathic pain condition which may be sensitive to opioids and it might well be that this portion of their pain represents a nerve trunk pain component. It is reasonable to assume that intact nociceptive nerve fibres, in a peripheral nerve or a root, subjected to local pressure will fire in a relatively normal fashion, similar to that in response to a peripheral noxious stimulus; this type of activation would be perfectly well controlled by opioids. However, in the case of a permanent damage or dysfunction (with hyperpathia) of peripheral or central nervous structures, the perception of pain may be generated by different and aberrant mechanisms. All evidence available to date from anecdotal reports and systematic controlled studies indicates that such pain unfortunately appears to be unresponsive to opioids. Most of the issues which ought to be further explored and which were presented in the paper by Portenoy et al. were in fact discussed in our article, e.g., differential responsiveness to different opioids, subgroups of receptors, importance of dosage with relation to individual sensitivity, etc. We fully agree that opioids should never be withheld from any patient with severe pain. Also a lack of response with moderate or heavy doses should not stop further trials with even higher doses. However, this philosophy in combating pain should never lead us to disregard scientific data even though such knowledge ‘would contribute to the bias against opioids.’ Instead, our common goal should be to discover for which pain conditions opioids are effective and when they are not to find new remedies, pharmacological or others, for pain which appears to be inherently unresponsive to opioids.
5 Ashury.
Keferences
A.K.
damage: I ArnCr. S. and Meyerxon. on ncuropathic
B.A.. Lack of analgesic effect of opioids
and idiopathic
forms of pain.
Pain.
23 (IWXI
Al-nb.
S. and Meycrson.
B.A..
Reply
‘(‘iin opiates relieve neuropathic 3 A&r.
S. and Meyerson.
B.A..
to Howard
L.. Fields
on
pain’?‘, Pain. 35 (1488) 366 -367. Reply to Dr. Vecht‘\
comments.
il.l...
S.. Bertlcr.
Management
K..
Boluntl.
C.
of Pain in the Terminal
dations from the Swedish National i\llmiinn:i
Fiirlaget.
lorthes
Stockholm.
and
Meyerson.
Stage of Life.
Board of Health
19x4. pp. 47.
B.A..
The
Recommenand Welfare.
Can Y..
and
Overview. X Stcrnbach,
