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Brief Report   |    
Use of Topical Application of Lidocaine-Prilocaine Cream to Reduce Injection-Site Pain of Depot Antipsychotics
Yuval Bloch, M.D.; Yechiel Levkovitz, M.D.; Alexander Atshuler, M.D.; Vera Dvoretzki, Psych.R.N.; Shmuel Fenning, M.D.; Gideon Ratzoni, M.D.
Psychiatric Services 2004; doi: 10.1176/appi.ps.55.8.940

This study took place in Israel and examined the use of a local topical anesthetic cream to ameliorate the pain at the injection site caused by depot antipsychotic medications. Fifteen consecutive outpatients who had schizophrenia and who were under treatment with depot antipsychotic medications were enrolled in this randomized, double-blind, placebo-controlled crossover study. The patients received either lidocaine-prilocaine cream or a placebo one hour before the injection. The degree of pain at the injection site was quantified by the patients' use of a visual analogue scale five minutes after the injection. The application of the lidocaine-prilocaine cream led to a significant reduction of pain compared with the placebo.

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Depot antipsychotic medications are one way of facilitating and monitoring medication compliance among patients with schizophrenia (1), which reduces relapse rates (2). However, this type of therapy tends to be avoided because of patients' unsupported fear of more side effects, patients' sense of being overly controlled, and the pain or discomfort at the injection site that some patients experience (1). A recent study found that the severity of pain that patients experienced during an injection was correlated with their attitude toward the injection (3), and thus depot-associated pain might affect patient compliance as well.

Lidocaine-prilocaine cream has enjoyed increasing popularity as a local anesthetic to prevent pain from various minor medical and surgical procedures, including intramuscular injections, without aggravating anticipatory anxiety (4,5). We explored whether use of this cream can ease the pain that is related to depot injections among patients with schizophrenia.

During 1999 a total of 15 consecutive patients from a mental health center gave informed consent to participate. Entrance criteria included being an outpatient, being aged 16 to 65 years, having a diagnosis of schizophrenia or a schizoaffective disorder from two senior psychiatrists according to DSM-IV criteria, and being treated with the same long-acting depot medication for at least two months. The study was approved by the institutional Helsinki Committee.

The patients' clinical condition was quantified with the Clinical Global Impression (CGI) (6), the Brief Psychiatric Rating Scale (BPRS) (7), the Hamilton Rating Scale for Depression (HAM-D) (8), the Hamilton Rating Scale for Anxiety (HAM-A) (9), and the Extrapyramidal Symptom Rating Scale (ESRS) (6). Possible scores on the CGI range from 1 to 7, with higher scores indicating more severe symptoms. Possible scores on the BPRS range from 18 to 126, with higher scores indicating increased severity of symptoms. Possible scores on the HAM-D range from 0 to 52, with higher scores indicating more severe depression. Possible scores of the HAM-A range from 0 to 56, with higher scores indicating more severe anxiety. Possible scores on the ESRS range from 0 to 36, with higher scores indicating more severe extrapyramidal symptoms. Patients used a visual analogue scale to quantify their pain at the injection site. The visual analogue scale is commonly used in pain studies and has been shown to reliably estimate quantitative aspects of pain (10). The scale ranges from 0 to 10, with 0 representing no pain and 10 representing maximal ("the most imaginable") pain.

Injections were given by the same nurse into the gluteus muscle by using a 21 G needle, a .1 air lock, and a double-needle technique. The Z technique was not used.

Participants were randomly assigned to groups by the flipping of a coin. For the first injection, the patients were assigned to receive lidocaine-prilocaine cream or a placebo one hour before receiving the depot antipsychotics in a double-blind, randomized fashion. For the next injection, the two treatment groups were crossed over. The placebo was a mineral oil cream that is ordinarily used to moisten dry skin. Both ointments were prepared on nylon patches, so the nurse and examiner were blind to treatment type. Each patient completed a visual analogue scale five minutes after each injection. A physician (AA) inspected the area for any local reaction.

To test the effect of treatment on pain, a 2 × 2 multivariate analysis of variance with a between-subjects factor of order (receipt of placebo first or the local anesthetic first) and a within-subject factor of treatment (placebo or local anesthetic) was performed on visual analogue scale measures. Correlations were tested with the Pearson correlation coefficient.

The study sample included 11 males (73 percent) and four females (27 percent) whose ages ranged between 23 and 58 years (mean±SD age of 42.4±7.9 years). Eleven patients (73 percent) had a diagnosis of schizophrenia (six had paranoid schizophrenia and five had unspecified schizophrenia), and four patients (27 percent) had a diagnosis of schizoaffective disorder. The range of illness duration was four to 28 years (mean of 16.7±6.6 years), and the number of hospitalizations ranged from one to14 (mean of 6.3±4.2 hospitalizations).

The patients' medical treatment consisted of haloperidol (two participants, or 13 percent), fluphenazine (nine participants, or 60 percent), and zuclopenthixol (four participants, or 27 percent). The injected volume of the antipsychotics ranged from .25 to 4 ml (mean of 1.2±.94 ml) and did not differ among the drugs. The patients' mental status on entry to the study indicated that they were actively psychotic (mean CGI score of 4±.53 and mean BPRS score of 40.9±9.6), that they had anxiety and depression (mean HAM-A score of 11.3±7.6 and mean HAM-D score of 13.7±5.4), and that they had some extrapyramidal side effects (mean ESRS score of 4.2±3.8).

An analysis of variance that was performed on visual analogue scale measures demonstrated a significant treatment effect (F=20.47, df=1, 13, p<.001), indicating that the local anesthetic led to a substantial reduction of pain compared with the placebo. The mean score on the visual analogue scale was .38±.6 for patients who received the local anesthetic first, compared with 4.3±3.1 for patients who received the placebo first, and .7±.82 for patients who received the local anesthetic second, compared with 2.2±1.9 for patients who received the placebo second. No significant order effect was seen whether the patient received the local anesthetic first or the placebo first, and no order by treatment interaction was observed. No significant correlations were observed between the injected volumes of the depot antipsychotics and the visual analogue scale measures after either the placebo or the anesthetic was applied.

The physician's impression of the injected area was that only one subject had mild rubor that resulted from the use of the local anesthetic. The rubor cleared within 30 minutes.

In this randomized, double-blind placebo-controlled crossover study the application of a local anesthetic reduced the minor pain at the injection site that was caused by depot antipsychotics. This finding is important for patients with schizophrenia who are using depot antipsychotics, who will need repeated injections throughout long-term therapy. Moreover, because a considerable number of patients with schizophrenia are characteristically noncompliant (1), the possibility of ameliorating pain from injections might have a parallel beneficial effect in enhancing medication compliance. Although our study did not examine long-term effect and compliance, the fact that one of our previous studies (3) showed a correlation between the pain that patients' experienced from an injection and their attitude toward the injection leads one to believe that the use of a local anesthetic could facilitate medication compliance. Although there are beneficial effects of using a local anesthetic cream, one should note that there is the inconvenience of waiting an hour to give the injection after the cream is applied. In clinical practice this waiting period can be managed by giving patients the possibility of applying the local anesthetic cream at home, either by themselves or with the help of caregivers. The limitations of the study include the small sample, the short follow-up, and the fact that compliance was not monitored. Our study was a pilot study. Long-term follow-up studies to monitor how patients' compliance with depot antipsychotics is affected by the use of local anesthetics are needed to test the clinical usefulness of this type of therapy.

The authors thank Gal Gilad, Ph.D., for his assistance in the statistical analysis.

The authors are affiliated with the Child and Adolescent Outpatient Clinic in Shalvata, Hod Hasharon, P.O. Box 94, Israel (e-mail, blochy@netvision.net.il).

Kane JM, Aguglia E, Altamura AC, et al: Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology 8:55—66,  1998
[PubMed]
[CrossRef]
 
Davis JM, Matalon L, Watanabe MD, et al: Depot antipsychotic drugs: place in therapy. Drugs 47:741—773,  1994
[PubMed]
[CrossRef]
 
Bloch Y, Mendelovic S, Strupinsky S, et al: Injections of depot antipsychotics medications in patients suffering from schizophrenia: do they hurt? Journal of Clinical Psychiatry 62:855—859,  2001
 
Cassidy KL, Reid GJ, McGrath PJ, et al. A randomized double-blind, placebo-controlled trial of the EMLA patch for the reduction of pain associated with intramuscular injection in four to six-year-old children. Acta Paediatrica 90:1329—1336,  2001
[PubMed]
[CrossRef]
 
Himelstein BP, Cnaan A, Blackall CS, et al: Topical application of lidocaine-prilocaine (EMLA) cream reduces the pain of intramuscular infiltration of saline solution. Journal of Pediatrics 129:718—721,  1996
[PubMed]
[CrossRef]
 
Guy W: ECDEU Assessment Manual for Psychopharmacology, Revised. Pub no ADM 76—338. Rockville, Md, US Department of Health, Education and Welfare, National Institute of Mental Health, 1976
 
Faustman WO, Overall JW: Brief Psychiatric Rating Scale, in The Use of Psychological Testing for Treatment Planning and Outcome Assessment, 2nd ed. Edited by Maruish M. Mahwah, NJ Lawrence Erlbawm, 1999
 
Hamilton M: A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 23:56—62,  1960
[PubMed]
[CrossRef]
 
Hamilton M: The assessment of anxiety states by rating. British Journal of Medical Psychology 32:50—55,  1959
[PubMed]
[CrossRef]
 
Moore A, Moore O, Mcquay H, et al: Deriving dichotomous measures from continuous data in randomized controlled trials of analgesics: use of pain intensity and visual analogue scales. Pain 67:311—315,  1997
 
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References

Kane JM, Aguglia E, Altamura AC, et al: Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology 8:55—66,  1998
[PubMed]
[CrossRef]
 
Davis JM, Matalon L, Watanabe MD, et al: Depot antipsychotic drugs: place in therapy. Drugs 47:741—773,  1994
[PubMed]
[CrossRef]
 
Bloch Y, Mendelovic S, Strupinsky S, et al: Injections of depot antipsychotics medications in patients suffering from schizophrenia: do they hurt? Journal of Clinical Psychiatry 62:855—859,  2001
 
Cassidy KL, Reid GJ, McGrath PJ, et al. A randomized double-blind, placebo-controlled trial of the EMLA patch for the reduction of pain associated with intramuscular injection in four to six-year-old children. Acta Paediatrica 90:1329—1336,  2001
[PubMed]
[CrossRef]
 
Himelstein BP, Cnaan A, Blackall CS, et al: Topical application of lidocaine-prilocaine (EMLA) cream reduces the pain of intramuscular infiltration of saline solution. Journal of Pediatrics 129:718—721,  1996
[PubMed]
[CrossRef]
 
Guy W: ECDEU Assessment Manual for Psychopharmacology, Revised. Pub no ADM 76—338. Rockville, Md, US Department of Health, Education and Welfare, National Institute of Mental Health, 1976
 
Faustman WO, Overall JW: Brief Psychiatric Rating Scale, in The Use of Psychological Testing for Treatment Planning and Outcome Assessment, 2nd ed. Edited by Maruish M. Mahwah, NJ Lawrence Erlbawm, 1999
 
Hamilton M: A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 23:56—62,  1960
[PubMed]
[CrossRef]
 
Hamilton M: The assessment of anxiety states by rating. British Journal of Medical Psychology 32:50—55,  1959
[PubMed]
[CrossRef]
 
Moore A, Moore O, Mcquay H, et al: Deriving dichotomous measures from continuous data in randomized controlled trials of analgesics: use of pain intensity and visual analogue scales. Pain 67:311—315,  1997
 
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