Vol. 13 No. 6June 1997 Letters 315

subcutaneous morphine in cancer pain: a random- ized evaluation. J Clin Oncol 1995;13(6):1520-1527.

3. Bruera E, Fainsinger R, Spachynski K, Babul N, Harsanyi Z, Darke AC. Steady-state pharmacoki- netic evaluation of a novel controlled release mor- phine suppository and subcutaneous morphine in cancer pain. J Clin Pharmacol 1995;35:666-672.

4. Darke AC, Moulin D, Provencher L, Laberge F, Harsanyi Z, Babul N. Efficacy, safety and pharmaco- kinetics of controlled release morphine supposito- ries and tablets in cancer pain. Clin Pharmacol Ther 1995;57:165.

Ketorolac: Continuous Subcutaneous Infusion for Cancer Pain

To the Editor: Following the case report by Middleton e t al. 1

about the use of ketorolac by continuous intrave- nous infusion, we would like to describe our experience of using ketorolac by subcutaneous infusion in patients with pain due to cancer. The indication was pain predominantly of bony ori- gin, which occurred in (a) acute situations while awaiting fur ther investigation and definitive management (for example, radiotherapy) and (b) l onge r t e r m si tuat ions in which pa in remained unrelieved despite full use of other conventional therapies.

Ove r a 15 -mon th pe r iod , s u b c u t a n e o u s ketorolac was used in 30 separate episodes of pain in 25 patients (12 male). The mean age was 65 years (range, 43 to 83) and the diagnoses varied: breast (6), prostate (4), renal (3), blad- der (3), lung (2), and other (7). None had a history of peptic ulcer disease. One pat ient already taking a nonsteroidal antiinflammatory drug (NSAID) and diuretics had mild renal impairment, which was unchanged after 9 days of ketorolac. Another patient with preexisting mild hematuria from bladder cancer was treated with ketorolac 90 mg for 185 days, the analgesic benefit outweighing the problem of hematuria. Pain was severe and uncontrolled despite the use of an opioid in all episodes and the use of oral NSAIDs in 27 episodes.

Usually, patients were commenced on ketoro- lac 60 mg diluted in normal saline over 24 hours via a Graseby syringe driver. Where necessary, the dose was increased to 90 mg to achieve improvement in analgesia. All patients were pre- scribed prophylactic misoprostol (200 pg four

times daily) or omeprazole (20 mg daily: six epi- sodes).

Pain improved in 27 episodes. In 7, pain relief was associated with increased mobility and function. A reduct ion (-->25%) in opioid analgesia was possible in 3 episodes. The maxi- m u m dose of ketorolac was 90 mg in 15 epi- sodes, 75 mg in 6 episodes, and 60 mg in 9 episodes. In 7 of 10 episodes, pain re tu rned following conversion to an oral NSAID. This event necessitated a resumpt ion of ketorolac.

The mean durat ion of t rea tment was 20 days (median 12 days; range 3 to 185 days). Over- all, ketorolac was well tolerated. The following adverse effects each occurred once: melena in an 81-year-old after 22 days at 75 nag per day and local rectal bleeding in a 67-year-old after 27 days of 90 mg per day. Both events resolved on s t opp ing the ke to ro lac . T h e o t h e r 10 patients over 65 years old (14 pain episodes) to lera ted ketorolac wi thout p rob lems for a mean dura t ion of 10 days (median 9 days; range 3 to 36 days).

Ketorolac 60 m g and 90 mg have b e e n mixed with d iamorphine 260 mg and 160 mg, respectively, in normal saline with no physical evidence of incompatibil i ty or loss of clinical effect. The re have been no p rob lems with local skin reactions. Ketorolac forms an imme- diate precipitate with midazolam, cyclizine, or haloperidol.

In conclusion, we have found subcutaneous ketorolac to be a useful analgesic in patients with cancer whose pain has been difficult to relieve. Its use requires caution, and appropri- ate con t r a ind ica t ions should be observed . Despite the 48-hour limit to its use for postop- erative pain relief, we have found it to be well to lera ted in pat ients with advanced cancer over relatively long periods.

Andrew Hughes, MRCGP Senior Registrar in Palliative Medicine

and Andrew Wilcock, MRCP Senior Lecturer in Palliative Medicine & Oncolog T

and Ray Corcoran, FRCOG Medical Director and Consultant in Palliative Medicine Hayward House, Macmillan Palliative Care Unit Nottingham City Hospital, NHS Trust Nottingham, United Kingdom

PlI S0885-3924(97)00056-0

316 Letters Vol. 13 No. 6June 1997

Reference 1. Middleton Rig, LyleJA, Berger DL. Ketorolac con-

tinuous infusion: a case report and review of the litera- ture. J Pain Symptom Manage 1996;12:190-194.

Alkalinization Is Troublesome in Advanced Cancer Patients With Dyspnea

To the Editor: I read the article of the Japanese group rep-

resented by Taguchi et al.1 with interest. As the conclusions repor ted may have clinical impli- cations that disagree with the c o m m o n physi- ological mechanisms known to regulate respi- r a t o r y activity, the sugges t ions r e p o r t e d , a l though exper imenta l in the design, may be misleading. I would like to c o m m e n t on this observation.

Different mechanisms have been recognized for opioids. The effects of opioids are attrib- uted to a depression of this chemical control in central neurons, so that higher values of PCO 2 are necessary to stimulate ventilatory response and the ventilatory response curve is shifted to the right with a consequent decrease in m inu t e vo lume and resp i ra to ry rate. A decrease in metabolic consumpt ion has been advocated as an alternative mechanism.

Although control th rough chem orecep to r receptors occurs, the central response is the most impor tan t factor regulating respiration, and as a consequence, mo to r c o m m a n d signal, th rough the carbon dioxide. At rest, the loga- r i thm of pu lmona ry ventilation is correlated with the cerebrospinal fluid (CSF) H + con- centration, assimilable to the interstitial fluid contacting the respiratory neurons. This ratio is unchanged both by bicarbonates in plasma and CSF, as bicarbonate concentrat ion gradi- ents between b lood and CSF are mainta ined by an ionic pump. Increases in the arterial PCO 2 result in a cor responden t augmenta t ion in CSF PCO 2 with a delay in the ventilatory response to changes in PCO 2 due to ar ter ial- CSF equilibration time. As CSF acidification stimulates ventilation similar to the inhalation of carbon dioxide, the central response to car- bon dioxide can be expressed as a linear func- tion of the CSF H + concentrat ion. 2 On the

o ther hand, it is well known that alkalinization by bicarbonates induces an increase in respira- tory acids, and as a consequence, the forma- t ion of ca rbon dioxide f rom H2CO 3. This results in an increase in ventilatory response, shifting the PCO2/vent i la t ion curve toward the left. Patients with high values of PCO 2 can- not tolerate this fur ther workload to eliminate fur ther amounts of carbon dioxide.

The work seems to be suggested by an old o b s e r v a t i o n on the e f fec t o f b i c a r b o n a t e administrat ion on respiration in the presence of hyperoxia. ~ The authors hypothes ize an indirect effect on the central nervous system to depress ventilation. However, a reduct ion in the ventilatory drive during metabolic alkalo- sis, similar to the central mechanism proposed for opioids, is claimed as an explanation.

No c lear e x p l a n a t i o n can be f o u n d to explain the results shown by Taguchi et al. 1 Although high values of PO 2 have a limited effect, even small decreases in PO2, observed in the exper iment after provoking alkalosis, 1 no rma l ly d e t e r m i n e a left shift o f PCO2/ ventilation curve with an increase in the slope. Moreover, mainly due to technical problems such as the use of large valves in the system, high differences have been repor ted in mea- suring such curves, depend ing on rebreath- ing. The time that elapsed between the mea- surements may be too short to evidence the effects of bicarbonate administrat ion on the breathing pattern, considering the well-known delayed onset of the ventilatory response to PCO 2 changes. In any case, data in normal subjects canno t be ex t rapola ted to patients with respiratory or advanced disease, as the character of ventilatory control is due to dif- ferent driving forces depending on the neuro- logical status, integri ty of neura l pathways, muscular force, residual capacity and dead space, intrathoracic pressure, t ransmural gra- dients, pu lmonary reflexes, static and dynamic compliance, reduct ion of the alveolar surfac- tant, gas tu rbu lence and resp i ra to ry resis- t a n c e s , d i f f e r e n t c a r b a m i n i c t r a n s p o r t (Haldane 's effect) due to low hemoglob in lev- els, and so on.

The authors are aware of these consider- ations, as they conclude that artificial alkalosis in dyspneic patients may fur ther deteriorate