Opioids, benzodiazepines and Z drugs are important and widely used drugs, but are associated with a risk of misuse, abuse and adverse effects. In some situations, serum concentration measurement may be useful to optimise treatment and detect misuse. In this article we show how such measurements can best be used, and present new reference ranges for these substances in serum, devised by the Norwegian Association of Clinical Pharmacology.
Addictive drugs such as opioids, benzodiazepines and Z drugs differ from other drugs in that they lead to development of tolerance and may lead to dependence and abuse. The substances have a significant level of toxicity and a risk of interacting with each other and with other central nervous system depressants such as alcohol. They also reduce cognitive and psychomotor skills and increase the risk of traffic accidents. Therefore, it is often appropriate for patients to use the lowest possible doses for the shortest possible period – and in many cases only as needed. However, the fact is that many patients use addictive drugs more or less permanently (1 – 3). In some patients, tolerance may develop over time, which leads to an increase in dosage. It is therefore difficult to define a therapeutic dose range, particularly for patients who need to use strong opioids over a longer period. Moreover, the dose requirement for opioids will vary considerably based on the type and degree of pain.
The use of serum concentration measurements to guide drug therapy is known as «therapeutic drug monitoring» (TDM). Serum concentration measurements may be considered useful when various clinical issues arise regarding the use of addictive drugs, such as therapeutic failure or adverse effects, unexpectedly strong or weak effect of a given dosage, or if overdose or toxicity is suspected. However, it is our experience that monitoring of adherence, i.e. whether patients keep to the prescribed dose, is the most frequent reason to order serum measurements of addictive drugs. For such measurements to have relevance, the serum concentration measured must necessarily be related to and interpreted in the light of a reference range.
Reference ranges for drugs
There is no unanimously accepted definition for the term «reference range» in TDM. For some drugs, the reference range will reflect the range of concentrations which most often provide a favourable relationship between efficacy and adverse effects. In these cases, the reference range is referred to as a therapeutic range. Well-known examples are aminoglycosides, methotrexate and digoxin.
Serum concentration measurements are also used for a number of drugs for which no defined therapeutic ranges are available, but for which we lack immediate clinical measurements of therapeutic effect. Examples of these are many antidepressants and antipsychotics, in addition to some newer antiepileptic drugs. For these types of drugs, the reference range is defined on a pharmacokinetic basis and reflects the range of concentrations that is normally achieved with the use of therapeutic doses (4). The reference range is then calculated based on a large number of measurements in a patient population, where the lower and upper limits for example correspond to the 10th and 90th percentiles of serum concentrations when therapeutic doses are used.
Although it has long been possible to measure the serum concentration of opioids, benzodiazepines and Z drugs, no well-defined reference ranges for these substances have previously existed. Published compilations of reference ranges are frequently discordant, and often little information is available with regard to the basis for the reference ranges, and how test results should be interpreted in light of these (4, 5). As a result, the pharmacological laboratories have lacked a solid basis on which to interpret serum concentration measurements and provide guidance for the requisitioning doctors, and different laboratories have specified different reference limits for these substances.
New reference ranges
In 2014, the Norwegian Association of Clinical Pharmacology established a working group to prepare common reference ranges for opioids, benzodiazepines and Z drugs. The launch of the Pharmacology Portal (6), a national web portal for pharmacological and toxicological analyses in Norway, made this work all the more necessary and the working group recently submitted its conclusion (Table 1 and Table 2) (7).
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Table 1 New upper reference limits for opioids. Upper reference limit corresponds to expected upper trough (pre-dose) concentrations using daily doses corresponding to 100 mg oral morphine equivalents (strong opioids), or highest daily dosage in the summary of product characteristics (weak opioids). The aim should be for the lowest effective dose. | ||
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Drug |
Upper reference limit |
Daily dose as basis for upper reference limit |
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Morphine |
34 ng/ml (120 nmol/l) |
100 mg |
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Oxycodone |
63 ng/ml (200 nmol/l) |
60 mg |
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Buprenorphine |
1.2 ng/ml (2,5 nmol/l)¹ Opioid substition: 0.9 – 4.7 ng/ml (2 – 10 nmol/l) |
2 mg (Higher doses for opioid substitution) |
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Fentanyl |
3.4 ng/ml (10 nmol/l)² |
1.2 mg (50 μg/h) |
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Ketobemidone |
74 ng/ml (300 nmol/l) |
100 mg |
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Pethidine |
700 ng/ml (2 800 nmol/l) |
1 000 mg |
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Codeine |
250 ng/ml (850 nmol/l) |
240 mg |
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Tramadol O-desmethyltramadol (active metabolite) |
790 ng/ml (3 000 nmol/l) 100 ng/ml (400 nmol/l)³ |
400 mg |
| [i] | ||
[i] ¹ Applies to sublingual administration. Low-dose transdermal buprenorphine seldom results in measurable serum concentrations with the methods of analysis used.
² Applies to transdermal use.
³ O-desmethyltramadol is an active metabolite of tramadol, and presumably mediates the main component of the opioid effect.
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Table 2 New upper reference limits for benzodiazepines and Z drugs. Upper reference limit corresponds to expected upper trough (pre-dose) concentrations, using the highest recommended daily dosage for anxiety/restlessness and/or insomnia. The aim should be for the lowest possible dose and short-term/intermittent use | ||
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Drug |
Upper reference limit |
Daily dose as basis for upper reference limit |
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Diazepam (incl. N-desmethyldiazepam) |
1 000 ng/ml (3 500 nmol/l)¹ |
15 mg |
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Oxazepam |
720 ng/ml (2 500 nmol/l) |
45 mg |
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Alprazolam |
50 ng/ml (160 nmol/l) |
3 mg |
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Clonazepam |
16 ng/ml (50 nmol/l) Epilepsy: 20 – 70 ng/ml (60 – 220 nmol/l) |
1.5 mg (Higher doses for epilepsy) |
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Nitrazepam |
84 ng/ml (300 nmol/l)² |
5 mg |
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Flunitrazepam |
6 ng/ml (20 nmol/l)² |
1 mg |
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Zopiclone |
20 ng/ml (50 nmol/l)² |
7,5 mg (5 mg in the elderly) |
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Zolpidem |
30 ng/ml (100 nmol/l)² |
10 mg (5 mg in the elderly) |
| [i] | ||
[i] ¹ Diazepam converts to the active metabolite N-desmethyldiazepam, which is also quantified. Upper reference limit applies to the sum of diazepam plus N-desmethyldiazepam.
² Upper reference limit for Z drugs and benzodiazepines for insomnia applies to samples taken a minimum of 12 hours after intake.
Since the therapeutic effect will largely depend on the patient’s primary condition and the individual degree of tolerance, it is difficult to define therapeutic ranges for these drugs. Instead, the working group considered that upper reference limits should reflect the expected upper trough (pre-dose) concentrations, using the highest daily dosage for the main indications for these groups of substances – treatment of pain for opioids, and of anxiety and insomnia for benzodiazepines and Z drugs, respectively. Lower reference limits were not considered appropriate, as the serum concentration for these drugs should generally be kept as low as possible. The highest daily dosage of weak opioids, Z drugs and benzodiazepines was defined on the basis of the recommended doses given in Norwegian or Swedish summaries of product characteristics (SPCs). There is no well-defined maximum dose for strong opioids. We chose equianalgesic doses corresponding to 100 mg oral morphine daily (8) as a basis for calculating upper reference limits for strong opioids, since the great majority of those using opioids over a longer period will use lower doses (1). The doses are rounded to the nearest practical daily dosage for marketed drug formulations. The calculation of upper reference limits from the defined upper daily dosages is based on a review of published pharmacokinetic studies and the laboratories’ own TDM databases.
BOX 1
Indications for serum concentration measurement of addictive drugs
Monitoring of drug adherence
Therapeutic failure at standard dosage
Unexpected or pronounced adverse effects at standard dosage
Suspected overdose or symptoms of intoxication
Diagnosis of misuse/abuse (urine samples usually more suitable)
Recommendations for use
With the new reference limits that have been established, the laboratories are better equipped to interpret serum concentration measurements of addictive drugs. In the great majority of cases, patients who keep within the recommended dose range will have trough serum concentrations lower than the reference limit. Concentrations above the reference limit may indicate use of higher doses than recommended, having excluded the possibility of inappropriate sampling time. There is nevertheless a significant variation from patient to patient, and many factors may affect the relationship between serum concentration and dosage. Impaired organ function or age-related pharmacokinetic changes may increase the serum concentration, while drug interactions and genetically determined deviations in drug metabolism may yield higher or lower serum concentration than expected.
When ordering serum concentration measurements, doctors should ensure that the samples as far as possible are taken at trough level, in other words, immediately before the next dose. Samples taken close to peak concentration will be misleading and cannot be compared to the reference limits. Information on dosage, time of last intake and time of sampling must be provided for the laboratory to be able to give an interpretation of the test result, including whether the measured serum concentration is consistent with the given dosage. We recommend contacting the laboratory in question in case of doubt as to how the serum concentration measurements should be interpreted, and preferably in advance of the sample being taken if there is any question regarding the procedure.
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