Pill Counts vs. Pharmacology: What Pharmacists and Referring Physicians Should Know

This is an argument that comes up several times a month, usually with a pharmacist, occasionally with
an insurer, sometimes with a regulator. They look at a patient on thirty-day quantities of a short-acting
opioid, see a large number of individual tablets, and ask a reasonable-sounding question: why not
consolidate? One long-acting tablet, twice a day. Fewer units, less to divert, better-looking numbers.

Our answer is no — deliberately, in writing, and with reasons. This page is written for pharmacists,
referring physicians and dispensing partners, and it is deliberately public. We do not describe this
practice one way to clinicians and another way to the people we treat.

Where the pressure comes from

It is worth being honest that this pressure is not primarily clinical. It is metric pressure.
Enforcement actions and news coverage quote raw tablet numbers because raw tablet numbers are vivid;
nobody writes a headline about morphine milligram equivalents. A practice with high unit counts therefore
looks dangerous even when total exposure is low, and a practice that consolidates onto fewer, stronger,
longer-acting units looks responsible even when total exposure is higher. That is an optics problem being
solved with pharmacology.

The pressure on pharmacies is real and we do not dismiss it. Major chains have faced substantial
liability over opioid dispensing, and pharmacists carry genuine corresponding-responsibility exposure —
sometimes while being squeezed by their own employers. When a pharmacist pushes back on one of our
prescriptions we do not assume bad faith. We assume they are carrying risk they did not create. But we
still have to answer for the pharmacology.

The mechanistic argument, and its limits

The mu-opioid receptor is built to be stimulated intermittently — bind, signal, desensitise, recover,
resensitise. A long-acting formulation is specifically engineered to eliminate the trough. That is its
selling point: smooth, continuous plasma levels with no peaks or valleys. But the valley is not a defect;
the valley is when the receptor recovers. Continuous occupancy means continuous desensitisation pressure
and no resensitisation window. The receptor-level detail is set out in why long-acting opioids can make pain worse.

We label this honestly as mechanistic rationale. Birdsong and colleagues described the phosphorylation
and beta-arrestin machinery in cellular work, not in patients, and a randomised trial of sustained-release
morphine found tolerance without demonstrable hyperalgesia. If mechanism were all we had, a sceptical
pharmacist would be right to be unimpressed.

What the outcome data shows

So here is the outcome data, which is the stronger part of the case. Ray and colleagues published in
JAMA in 2016: long-acting opioid prescriptions were associated with significantly increased total
mortality compared with short-acting agents, and critically the excess was not confined to overdose —
there was excess cardiovascular and other non-overdose mortality, consistent with sustained systemic
exposure rather than a single acute event. Miller and colleagues published in JAMA Internal
Medicine in 2015: long-acting agents were associated with higher unintentional overdose risk, with
risk especially elevated early in treatment.

The caveat belongs in the same breath. Both are observational. Patients placed on long-acting opioids
may be more severe to begin with, so confounding by indication cannot be excluded and neither study
establishes causation. What we do claim is narrower: when the mechanistic reasoning and the large-scale
outcome data point the same way, and the argument for the alternative is that the unit count looks tidier,
the burden of proof does not sit with us.

The numbers we actually run

“Low total dose” is meaningless without figures. Our average patient is maintained at
approximately 27 to 32.5 MME, with typical dosing under 30 to 40 MME. Fewer than 1% sit
above 90 MME, and those are specific situations — active cancer pain under co-management, or postoperative
failed back surgery syndrome and arachnoiditis — where the elevated dose is a temporising measure during
reduction rather than a maintenance strategy. We frequently inherit patients at 400 to 500 MME and taper
them to a routine dose within one to three months. These are practice-reported figures from our own
population, not trial outcomes, and individual results vary.

There is also a deliberate safety design in the dispensing pattern itself: we do not dispense more
medication than a patient could foreseeably overdose on at one time. That produces more tablets on paper
and less risk in practice.

Does lower dosing produce better outcomes?

This is the right question. The SPACE randomised trial, published by Krebs and colleagues in
JAMA in 2018, compared opioids with non-opioid medication for chronic back pain and hip or knee
osteoarthritis pain: opioids were not superior for pain-related function over twelve months, and the
opioid group had more adverse events. High-dose therapy is not buying the functional benefit that
escalation implies.

The regulatory position has moved the same way. The CDC’s 2022 clinical practice guideline deliberately
removed the rigid dose thresholds that the 2016 version had been misapplied as hard caps, replacing them
with individualised decision-making, and it explicitly warns against abrupt or rapid reduction in patients
on long-term therapy. That matters because the opposite failure is also lethal: Fenton and colleagues found
tapering associated with increased long-term risk of overdose and mental health crisis. This is not an
argument for aggressive cuts. It is an argument for a low, stable, intermittent dose reached gradually,
with real treatment underneath it.

Where the real safety lives

“Fewer pills is safer” only sounds true if everything else in the system is ignored. A
tablet count is a static number on a page; safety is a process. Ours is built from frequency and
verification rather than unit reduction:

• Patients on long-term controlled substances are seen in person every two weeks. We do
  not provide telehealth for this population.
• Every patient brings every bottle to every visit for a physical count.
• Urine drug testing runs every six to twelve weeks, sent to an independent high-complexity laboratory
  using gas chromatography rather than a moderate-complexity immunoassay. Absence of the prescribed drug is
  treated as seriously as the presence of an illicit one.
• Every prescription is electronic. We issue no verbal orders and no telephoned prescriptions.
• Every patient signs a medication agreement with a single designated pharmacy, no early fills, and no
  controlled substances from other prescribers without telling us. Violations end the treatment
  relationship.

Compare the two models honestly. One patient collects sixty tablets a month and is seen twice, counted
twice and screened regularly. Another collects fourteen long-acting tablets and is seen once a quarter.
The unit count is the least informative number in that comparison.

What we ask of dispensing partners

Call us — and tell us what you see at the counter. Patients often present appropriately in clinic and
behave differently at a pharmacy, where their guard is down. That information is not otherwise available
to us and we act on it; credible reports of aberrant behaviour end the treatment relationship. Your
corresponding responsibility and ours point in the same direction.

The full protocol — monitoring, urine drug testing, PDMP use, agreement terms and discharge criteria —
is published as our opioid stewardship protocol. Related reading for patients: Is your pain medication making your pain worse? and Opioid bankruptcy: why opioids stop working. See also interventional pain management in St. Louis.

Frequently asked questions

If the pill count went down, isn’t that safer?

Not necessarily. Unit count and pharmacological risk are different measures. Consolidating a patient onto fewer, longer-acting units lowers the tablet number while increasing continuous receptor occupancy. Total morphine milligram equivalent (MME) dose and the pattern of exposure matter more than how many tablets appear on the prescription.

What does the outcome data actually show about long-acting opioids?

Two large studies point the same way. Ray and colleagues reported in JAMA in 2016 that long-acting opioid prescriptions were associated with increased total mortality compared with short-acting agents, including excess non-overdose deaths. Miller and colleagues reported in JAMA Internal Medicine in 2015 that long-acting agents were associated with higher unintentional overdose risk, especially early in treatment. Both are observational, so confounding by indication cannot be excluded and neither establishes causation.

What MME do your patients typically receive?

Our average patient is maintained at approximately 27 to 32.5 MME, with typical dosing under 30 to 40 MME, and fewer than 1% above 90 MME. We frequently inherit patients from primary care at 400 to 500 MME and taper them deliberately, generally reaching a routine dose within one to three months. These are practice-reported figures from our own population rather than trial results, and individual results vary.

Is there evidence against your position?

Yes, and we cite it. A randomised, placebo-controlled trial of sustained-release morphine in chronic low-back pain found analgesic tolerance but no demonstrable hyperalgesia. That means the hyperalgesia argument for avoiding long-acting formulations is a clinical judgement rather than a settled fact, which is why we rest the case on the mortality and overdose data instead.

How should a pharmacist reach the prescriber?

Directly. The clinic is (314) 481-5000, and for urgent pharmacist queries Dr. Padda can be reached at (314) 852-5500 — text is fine — or by email at seva@padda.com. If a prescription from us looks wrong to you, please call before refusing the fill. We also operate a strict electronic-prescribing-only policy: if you receive a verbal or telephoned prescription purporting to come from this clinic, it did not come from us.

Where are you located and how do I make an appointment?

Padda Institute Center for Interventional Pain Management, 4477 Woodson Road, Suite 100, St. Louis, MO 63134. Book at painmd.tv/appointment/, call (314) 481-5000 or text (314) 886-5902.

Key takeaways

• Unit count and pharmacological risk are different measures; total MME and the pattern of exposure matter more.
• Long-acting formulations eliminate the trough that lets the mu-opioid receptor resensitise.
• Ray 2016 and Miller 2015 associate long-acting agents with higher mortality and overdose risk — both observational, neither causal.
• A randomised trial found tolerance without demonstrable hyperalgesia, so the mechanistic case is a clinical judgement, not settled fact.
• The SPACE trial found opioids were not superior for function at twelve months, and the CDC’s 2022 guideline removed rigid dose caps.
• Aggressive tapering is the opposite failure and carries its own overdose and mental-health risk.
• Real safety comes from visit frequency, bottle checks, gas chromatography testing and electronic prescribing — not from a lower tablet number.

Medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP — Board Certified in Anesthesiology, Pain Medicine, Interventional Pain Management, Addiction Medicine, and Obesity Medicine. Last reviewed July 2026.

This article is educational and is not a substitute for evaluation, diagnosis, or treatment by a physician. Individual results vary. Do not start, stop, or change any medication without consulting your physician. Opioid withdrawal can be medically hazardous and abrupt discontinuation carries real risk.

References

1. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain. JAMA. 2016;315(22):2415–23. PMID 27299617. Observational.
2. Miller M, Barber CW, Leatherman S, Fonda J, Hermos JA, Cho K. Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. JAMA Intern Med. 2015;175(4):608–15. PMID 25686208. Observational.
3. Birdsong WT, Arttamangkul S, Bunzow JR, Williams JT. Agonist binding and desensitization of the μ-opioid receptor is modulated by phosphorylation of the C-terminal tail domain. Mol Pharmacol. 2015;88(4):816–24. PMID 25934731. Cellular.
4. Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018;319(9):872–82. PMID 29509867.
5. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain — United States, 2022. MMWR Recomm Rep. 2022;71(3):1–95. PMID 36327391.
6. Fenton JJ, Magnan E, Tseregounis IE, Xing G, Agnoli AL, Tancredi DJ. Long-term risk of overdose or mental health crisis after opioid dose tapering. JAMA Netw Open. 2022;5(6):e2216726. PMID 35696163.
7. Fishbain DA, Pulikal A. Does opioid tapering in chronic pain patients result in improved pain or same pain vs increased pain at taper completion? A structured evidence-based systematic review. Pain Med. 2019;20(11):2179–97. PMID 30597076.
8. Chu LF, D’Arcy N, Brady C, et al. Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for chronic nonradicular low-back pain. Pain. 2012;153(8):1583–92. PMID 22704854. Counter-evidence.

Dr. Gurpreet Singh Padda, MD, MBA, MHP , MD, MBA, MHP