Dilaudid in Detail: The Problem with Hydromorphone

Pain expert Sergey Motov speaks with EPM editor Nicholas Genes about the do’s and don’ts of using hydromorphone (Dilaudid) for pain care in the emergency department.

Nicholas Genes, MD, PhD
You gave a talk recently, citing that US ED use of hydromorphone essentially doubled from 2005-2010. These cover the years I was in training, when I was reading the literature and listening to pain researchers. A number of us were really buying into Dilaudid! The two big selling points for Dilaudid that I remember from those years are a) faster onset and b) 1 mg of Dilaudid is an easy, round number – a more appropriate dose for today’s bigger American, than say, 4 or 6mg of morphine.  But now, you’re saying these are good reasons NOT to give Dilaudid?

Sergey Motov, MD
Yes, as you pointed out, the ED hydromorphone (HM) use went up by 100% from 2005-2010, which was much larger than an increase for other opioids. [1] At the same time (from 2004 to 2011), there was a nationwide increase in therapeutic use of HM by 261% and an increase in misuse by 438% in tandem with an alarming increase in HM diversion, misuse and development of addiction. [2-4] The research supporting the use of hydromorphone in the ED that was conducted between 2006 and 2012 made ED clinicians even more “morphinophobic” and much more “hydromorphonophillic” because clinicians weren’t properly educated on efficacy and potency (equi-analgesic conversion) of hydromorphone and weren’t properly taught to use higher doses of morphine via titration. [5,6] Hydromorphone is about 8-11 times more potent (via IV) and 10 times more lipophilic than morphine – this translates into faster onset of analgesia. And a 1 mg dose is a rather large single dose of an opioid when administered to an opioid-naïve patient. ED clinicians are not routinely administering 8-10 mg of IV morphine, but that’s what 1 mg of hydromorphone amounts to.

Genes
I remember an argument along the lines of: “It’s easier to order 1mg of Dilaudid than to change the culture to get appropriate doses of morphine.” You’ve done work with nursing, for instance, on making it easier to infuse ketamine in the ED. Is culture really so hard to change? Culture of nurses, or the doctors, or something else?

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Motov
Unfortunately, it’s true. Several prominent EM research papers openly and misleadingly stated that “it would be easier to combat undertreatment of acute pain by introducing a different parenteral opioid such as hydromorphone rather than educate providers to use higher, more appropriately therapeutic doses of morphine.” [5,7]  ED clinicians listened and started to use hydromorphone on a much larger scale.

Changing the culture around ED use of hydromorphone for acute pain is now a herculean task because there is an observed and even published phenomenon amongst ED clinicians: too many of us believe that a smaller milligram dose (1-2 mg) of hydromorphone translates into a lesser total amount of opioid given to the patients. This phenomenon is really just a lack of appreciation for hydromorphone’s potency that sets us up for prescribing significantly larger doses of hydromorphone in comparison to morphine.

For example, a trial evaluating reasons that ED practitioners prescribe hydromorphone over morphine demonstrated that 46 percent of providers gave reasons without pharmacological validity. [8] In daily practice, this lack of understanding of hydromorphone potency leads to excessive hydromorphone dosing by 50-75% as these 1-2 mg doses of IV hydromorphone translate into 8-16 mg of IV morphine equivalents, resulting in serious adverse effects such as respiratory depression, CNS depression and hypotension. And more importantly, these are often patients where smaller doses of hydromorphone would’ve been adequate for analgesia and less risky.

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Genes
Ok, let’s compare efficacy and side effects. We can see from trial data and our own experience that hypotension, bradypnea/hypoxia and pruritis are worse with hydromorphone, compared to morphine. But how different is Dilaudid’s speed of onset, degree of pain relief, and half-life? Is it worth the trade-off?

Motov
The onset and duration of hydromorphone analgesia, with respect to its efficacy and potency, have not been conveyed to ED clinicians by available EM research at the extent it should have. When hydromorphone is administered in equianalgesic morphine milligram equivalents, it does not provide superior analgesia. However, in supra-equianalgesic doses (1-2 mg), hydromorphone does result in more pruritus, and it does accumulate in patients with renal failure.

But hydromorphone is 10 times more lipophilic than morphine, which allows it to more rapidly penetrate the blood brain barrier and saturate μ-receptors. This rapid receptor saturation leads to fast onset of analgesia and a shorter half-life of HM. [9]

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Genes
Looking back, it seems really odd to me that Demerol (meperidine) fell out of favor around the same time that we embraced Dilaudid (hydromorphone). I recall we removed it from our ED formulary right around the time I started seeing Dilaudid touted in the literature. Did we trade one euphoric drug for another?

Motov
You are correct. We have substituted one evil analgesic with another. The high lipophilicity of hydromorphone leads to fast penetration of the blood-brain barrier and results in very fast onset and offset of the pleasurable effects such as euphoria and tranquility. The repetitive desire to achieve euphoria leads to recreational use and misuse in dose-escalating pattern that culminates in development of an opioid use disorder and at times, overdose and death. [11,12] The higher abuse liability and likeability of hydromorphone leads to its misuse and a street value six times higher than morphine due to its potent euphoric effect.

Genes
When we recently discussed tramadol, it was easy to blame its rise in popularity on drug companies and marketing campaigns. What led to the rise in use of hydromorphone in the middle of the last decade? Was it our fellow academics, concerned about oligoanalgesia?

Motov
Hydromorphone’s initial use in clinical practice as an alternative to morphine was directed towards patients with intractable cancer pain and palliative care who could not achieve acceptable pain relief with large doses of morphine due to intolerable side effects such as nausea, pruritus and even delirium. [10] Unfortunately, due to a massive push by prominent societies and organizations for widespread use of opioids across multiple specialties for managing a variety of acute and chronic painful conditions – fueled by a concept of “oligoanalgesia,” – hydromorphone was brought into the emergency medicine.

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Another contributing factor leading to hydromorphone’s adoption in the ED was under-dosing and lack of titration of IV morphine, due to fears of severe respiratory depression. This is regrettable, because morphine has the best balance of analgesic efficacy and safety among available opioids based on extensive clinical experience as well as pharmacodynamic and pharmacokinetic data.

Finally, the research that proclaimed hydromorphone to be a safe and effective alternative to morphine didn’t fully describe its equi-analgesic efficacy and potency nor fully evaluate its abuse and misuse-prone potential or its more malignant side effects profile. All these factors have led to unwarranted “ED hydromorphonophilia” and a big uptick in orders and prescribing.

Genes
It’s one thing to cut down on ED clinicians ordering Dilaudid for naïve patients, but what about those already on Dilaudid PO doses coming into the ED with painful complaints? If we try to give them 8mg of morphine, the patients are incredulous. What to do?

Motov
To start, acknowledge their pain, and engage them in shared-decision making about their pain syndrome. Set expectations and try therapeutic modalities including non-opioid and, if warranted, opioid analgesics. Analgesics should be tailored to individual patients and considered based on their side effects. Practically speaking, consider ketorolac, sub-dissociative dose ketamine, ultrasound-guided regional block, IV lidocaine. If opioids are to be used, consider titration of IV morphine or IV fentanyl. When it comes to oral opioids, you and I have discussed this on numerous occasions. I am a big proponent for morphine sulfate immediate release (MSIR) tablets for acute pain – in the ED and at discharge. It’s not something we try often enough, and there’s evidence that MSIR has analgesic efficacy comparable to hydrocodone and oxycodone with less euphoria and potential for recreational use and abuse.

Now we have an opportunity to prescribe an efficacious and less abuse-prone opioid (MSIR) to our patients in the ED and at discharge when indicated and when benefits of doing so outweigh the risks associated with its use.

Genes
We’re also seeing a lot of Dilaudid patients asking for IV diphenhydramine. I’ve quoted our ED’s policy of PO Benadryl instead of IV to those on Dilaudid who want to avoid the pruritis. Every patient says IV is preferred… But what evidence do we have that PO diphenhydramine is as effective as IV diphenhydramine for curbing pruritis?

Motov
PO diphenhydramine is as effective as IV diphenhydramine but has variable solubility through GI tract. This can delay onset of action (around 30-45 minutes). However, the rates of anticholinergic adverse effects from PO diphenhydramine are less prominent. Diphenhydramine (in oral and parenteral forms) is not a recommended agent to relieve opioid-induced pruritus, as it contributes to excessive sedation when administered with opioids.

It’s worth mentioning that opioid-induced pruritus is predominantly Mu-receptor mediated, which is effectively treated by ultra-low dose of Naloxone at 0.25mcg/ kg/hr-1 mcg/kg/hr without excessive sedation, withdrawal and reduction in analgesic efficacy of opioids. [14]

Genes
So when it comes to Dilaudid use in the ED…

Motov
Hydromorphone lacks analgesic superiority over morphine when administered in equianalgesic doses. It gets prescribed in doses 50-75% higher than morphine equivalents, it causes severe respiratory and CNS depression, and it possess severe euphoric and abuse potential properties that leads to misuse, diversion and addiction. ED practitioners should be discouraged from routine use of hydromorphone in the ED for acute and exacerbation of chronic painful conditions. ED clinicians should promote safe and judicious hydromorphone administration in the ED by prescribing smaller effective doses and reserving it for patients with intractable, multi-analgesic-resistant painful conditions and palliation.

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