Converting to Transdermal Fentanyl: Avoidance of Underdosing

Abstract

Background:

Converting between the various opioid agents continues to be challenge for many practitioners. Specifically, variable recommendations for converting to the transdermal fentanyl patch may lead to confusion among clinicians and errors in dosing.

Objective:

Our aim was to describe the inconsistencies among available opioid conversions with regard to transdermal fentanyl and to provide recommendations for safe and effective utilization of this product in patients with chronic pain.

Results:

Available reports support the use of the morphine intravenous to oral ratio of 1:3 during the conversion to transdermal fentanyl product.

Conclusions:

Underdosing is an often overlooked complication of switching to transdermal fentanyl. Current recommendations for converting to transdermal fentanyl do not reflect contemporary clinical practice and should be reevaluated.

Introduction

Chronic pain is a common and feared symptom among patients with advanced illness.¹ Opioids are the mainstay of pharmacologic management of chronic pain and clinicians frequently convert between these agents. Many reasons exist for changing from one opioid to another, including lack of efficacy at a tolerable dose, renal or hepatic dysfunction, intolerable side effects, financial concerns, and route of administration.² Transdermal fentanyl is an especially good option for patients with persistent, moderate-to-severe chronic pain who are opioid tolerant. The unique delivery mechanism is also quite useful in patients unable to tolerate oral medication (mucositis, dysphagia, nausea/vomiting), or who have difficulty with compliance with an oral regimen, or a large pill burden.³

As with any opioid product, there exists potential for misuse and abuse with transdermal fentanyl. Whereas most of the literature focuses on the consequences of overdosing of opioids,⁴ which should still be emphasized, the issue of underdosing is also important. Underdosing in one series occurred in up to 50% of patients.⁵ Although underestimating the dosing of a long-acting opioid, such as transdermal fentanyl, might seem safe, these patients may experience excessive pain or withdrawal symptoms.⁴ Furthermore, underdosing can lead to a reduction in quality of life, fear of medication changes, mistrust in health care professionals, or even early termination of a new product as erroneously ineffective.⁶

A common concern for clinicians is appropriate conversion between different opioid agents because errors can lead to underdosing or overdosing, both of which can cause distress to the patient and frustration for the clinician. Making this process more difficult is potentially conflicting information surrounding the oral to intravenous morphine conversion ratio utilized in the transdermal fentanyl package insert. Based on clinical research in patients with acute pain, the historical conversion ratio for oral to intravenous morphine is 6:1.¹ However, although prospective evidence is not available for patients with chronic pain, a ratio of 3:1 is most often utilized in clinical practice.^3,7–8 As the first step in converting to the fentanyl patch is determining the patient's current 24-hour opioid total, often in morphine equivalents, this ratio can be extremely important.

Discussion

Analysis of available conversion references

No consensus guidelines exist for exact opioid conversions or equianalgesic dosing, mainly due to cross-tolerance, inter- and intrapatient variability, inherent differences in route of administration, and limitations of historical research.^4,7 Specifically, interpatient variability is marked with regard to transdermal fentanyl. The pharmacodynamics of the transdermal product can be influenced by several factors such as skin permeability, cachexia, patient sweating, and alterations in blood flow, for example due to the application of heat. Further, there is a paucity of data regarding how the pharmacokinetics of transdermal fentanyl are affected by differences in regional blood flow, protein binding, and altered clearance.^3,9 These variations can be most pronounced in patients with poor fat stores, muscle wasting, or cachexia, such as the elderly or debilitated patient populations.¹⁰

Based on exhaustive information regarding the substantial issues with available conversions as well as the increase in opioid overdosing leading to serious or fatal outcomes, there has been a recent recommendation to avoid conversion references all together and instead slowly titrate from one agent to another.⁸ However, this approach may not always be feasible with respect to transdermal fentanyl. Many patients who are converted to this specific product cannot tolerate oral medication and are therefore limited in breakthrough pain options necessitating a more rapid onset of pain relief with the transdermal product. Therefore, clinicians must appropriately interpret and apply conversion information from available references on a case-by-case basis.

One can assume the conservative 6:1 ratio utilized in Table E of the package insert³ for transdermal fentanyl is due to the lack of randomized, controlled trials confirming the safety of the 3:1 oral to intravenous (IV) morphine ratio in chronic pain patients. However, this 3:1 conversion ratio is often used in clinical practice and is referenced throughout the literature.^11,12 The package insert itself comments on the different available ratios, stating directly that “the conversion ratio of 10 mg parenteral morphine=30 mg oral morphine is based on clinical experience in patients with chronic pain. The conversion ratio of 10 mg parenteral morphine=60 mg oral morphine is based on a potency study in acute pain.”^1–3

The issue of the correct ratio comes into play when utilizing the conversion tables in clinical practice. If one uses the 3:1 ratio and then converts from IV morphine to the patch, it may result in a different dose than if one uses the 6:1 ratio. For example, when looking at Table C from the package insert of the transdermal fentanyl patch (see Table 1), we can clearly see that the oral to IV morphine ratio is 6 to 1.³ In a patient who is receiving a total of 80 mg per day of oral morphine, the patch size would be 25 mcg/hour if we use the oral morphine to fentanyl conversion from the package insert (Table C or E). However, if the total oral morphine of 80 mg per day was converted to IV morphine using the ratio of 3:1, which is felt to be more appropriate for patients who are already on opioids, then the use of Table C in the package insert will give a dose of 50 mcg/hour. This is a 100% dose difference simply by changing the morphine conversion ratio in the intermediate step. Because the ratio of 6:1 was established only for acute pain patients, many tertiary references, hospital conversion charts, and individual clinicians advise a 3:1 ratio.^11–14 It is important to note the fentanyl patch is only indicated for patients with chronic pain who are opioid tolerant.

Table 1.

Opioid Conversions

Analgesic	Daily dose
IV morphine (mg/day)	10–22	23–37	38–52	53–67
Oral morphine (6:1) (mg/day)^a	60–134	135–224	225–314	315–404
Oral morphine (3:1)(mg/day)^b	30–66	69–111	114–156	159–201
Transdermal fentanyl (mcg/hour)	25	50	75	100

As per transdermal fentanyl package insert.³

Recommended per 3:1 morphine oral:IV chronic pain ratio.

IV, intravenous.

Although no randomized trials have confirmed the 3:1 ratio, several studies have shown significant rates of underdosing when the 6:1 ratio is utilized. Sloan and colleagues¹⁵ evaluated the use of transdermal fentanyl in 53 adults with chronic cancer pain utilizing the visual analog scale to assess pain control. Using the 6:1 ratio to obtain the initial transdermal fentanyl dose, 72% of patients required a dose increase of the patch, 14% of these patients required a significant dose escalation, and 15% discontinued therapy due to inadequate pain relief, whereas only about 2% required a reduction in fentanyl dose.¹⁵ Likewise, an open-label study of 39 cancer patients with chronic pain using the same 6:1 ratio found that 50% of patients required a dose increase of the fentanyl patch, whereas none required a dose decrease.¹⁶ These studies suggest this 6:1 oral to intravenous morphine conversion is not adequate for the majority of patients with chronic pain and its utilization in calculating fentanyl patch doses may lead inadequate pain relief. Despite these studies suggesting underdosing with this methodology, the conversion from the package insert has been republished in several tertiary medical references to assist clinicians in practice.^17–19

Two other studies further support the concern that the current conversion recommendation to transdermal fentanyl is underdosing most patients. Donner and colleagues determined a ratio of 70:1 (70 mg oral morphine per day=1 mg transdermal fentanyl per day) in a small study of 38 adults with chronic cancer pain.²⁰ Furthermore, a review of six studies by Mercadante determined the ratio of 100:1 (100 mg oral morphine daily=1 mg transdermal fentanyl daily) was reliable and consistent.²¹ These ratios are in contrast to the package insert, which utilizes a 150:1 ratio (150 mg oral morphine per day=1 mg transdermal fentanyl per day).³

In addition to the potentially conflicting conversion recommendations made in the transdermal fentanyl package insert,³ various other conversions exist in the literature despite lack of quality studies confirming their accuracy.^2,6,18 Although for reasons stated above, there is not one correct conversion for all patients, clinicians must be aware of the differences between these recommendations.

Conversion recommendations

Based on this review, we recommend the following steps:

1. Only use transdermal fentanyl for patients with chronic pain who have a stable daily opioid dose.^3,22

2. Convert the current 24-hour total daily opioid use into IV morphine per 24-hour period.

a. If converting from oral to IV morphine in this step, we recommend using the 3:1 ratio.

3. Convert the 24-hour total IV morphine into transdermal fentanyl utilizing Table C from the product's package insert (adapted from Janssen Pharmaceutica Products package insert³).

IV morphine	Transdermal fentanyl
10–22	25 mcg/hour
23–37	50 mcg/hour
38–52	75 mcg/hour
53–67	100 mcg/hour

a. Be aware that Table E from the fentanyl patch package insert converts from oral morphine to the fentanyl patch using the 6:1 morphine oral to IV ratio.

b. Always use clinical judgment with regard to applying a percent dose reduction for cross-tolerance on an individual patient basis.³

4. Closely monitor for signs/symptoms of overdosing or underdosing.

a. Adjust patch dose as needed, keeping in mind the delayed impact of patch changes into systemic availability.

5. Use caution when converting from transdermal fentanyl to another opioid. No recommendations are available in product information.³

Conclusions

Although there are standards for dosing opioids, clinicians should critically evaluate available resources to ensure safe and effective opioid use. In general, the acute pain ratio for converting oral to IV morphine is not appropriate for chronic pain patients, such as those using the fentanyl patch. Caution should be taken when utilizing the fentanyl patch package insert conversion tables in order to avoid underdosing. When converting to the fentanyl patch, consideration of patient-specific factors and close monitoring are always warranted.

Author Disclosure Statement

No competing financial interests exist.

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